Tyk2 inhibitors and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful forinhibiting non-receptor tyrosine-protein kinase 2 (“TYK2”), also knownas Tyrosine kinase 2. The invention also provides pharmaceuticallyacceptable compositions comprising compounds of the present inventionand methods of using said compositions in the treatment of variousdisorders.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is the protein kinasefamily.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. Protein kinases are thought tohave evolved from a common ancestral gene due to the conservation oftheir structure and catalytic function. Almost all kinases contain asimilar 250-300 amino acid catalytic domain. The kinases may becategorized into families by the substrates they phosphorylate (e.g.,protein-tyrosine, protein-serine/threonine, lipids, etc.).

In general, protein kinases mediate intracellular signaling by effectinga phosphoryl transfer from a nucleoside triphosphate to a proteinacceptor that is involved in a signaling pathway. These phosphorylationevents act as molecular on/off switches that can modulate or regulatethe target protein biological function. These phosphorylation events areultimately triggered in response to a variety of extracellular and otherstimuli. Examples of such stimuli include environmental and chemicalstress signals (e.g., osmotic shock, heat shock, ultraviolet radiation,bacterial endotoxins, and H₂O₂), cytokines (e.g., interleukin-1 (IL-1),interleukin-8 (IL-8), and tumor necrosis factor α (TNF-α)), and growthfactors (e.g., granulocyte macrophage-colony-stimulating factor(GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulusmay affect one or more cellular responses related to cell growth,migration, differentiation, secretion of hormones, activation oftranscription factors, muscle contraction, glucose metabolism, controlof protein synthesis, and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggeredby kinase-mediated events. These diseases include, but are not limitedto, autoimmune diseases, inflammatory diseases, bone diseases, metabolicdiseases, neurological and neurodegenerative diseases, cancer,cardiovascular diseases, allergies and asthma, Alzheimer's disease, andhormone-related diseases. Accordingly, there remains a need to findprotein kinase inhibitors useful as therapeutic agents.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of TYK2 kinase.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with regulation of signalingpathways implicating TYK2 kinases. Such diseases, disorders, orconditions include those described herein.

Compounds provided by this invention are also useful for the study ofTYK2 enzymes in biological and pathological phenomena; the study ofintracellular signal transduction pathways occurring in bodily tissues;and the comparative evaluation of new TYK2 inhibitors or otherregulators of kinases, signaling pathways, and cytokine levels in vitroor in vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are usefulas inhibitors of TYK2 protein kinase.

The binding pocket of TYK2 contains a plurality of hydration sites, eachof which is occupied by a single molecule of water. Each of these watermolecules has a stability rating associated with it. As used herein, theterm “stability rating” refers to a numerical calculation whichincorporates the enthalpy, entropy, and free energy values associatedwith each water molecule. This stability rating allows for a measurabledetermination of the relative stability of water molecules that occupyhydration sites in the binding pocket of TYK2.

Water molecules occupying hydration sites in the binding pocket of TYK2having a stability rating of >2.5 kcal/mol are referred to as “unstablewaters.”

Without wishing to be bound by any particular theory, it is believedthat displacement or disruption of an unstable water molecule (i.e., awater molecule having a stability rating of >2.5 kcal/mol), orreplacement of a stable water (i.e., a water molecule having a stabilityrating of <1 kcal/mol), by an inhibitor results in tighter binding ofthat inhibitor. Accordingly, inhibitors designed to displace one or moreunstable water molecules (i.e., those unstable water molecules notdisplaced by any known inhibitor) will be a tighter binder and,therefore, more potent inhibitor as compared to an inhibitor that doesnot displace unstable water molecules.

It was surprisingly found that provided compounds displace or disruptone or more unstable water molecules. In some embodiments, a providedcompound displaces or disrupts at least two unstable water molecules.

In certain embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y,Ring A, L¹, R¹, R^(1′), R³, R⁴, and R⁵ is as defined below and describedin embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y,Ring A, L^(1′), R¹, R^(1′), R³, R⁴, and R⁵ is as defined below anddescribed in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula III:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y,Ring A, L¹, R¹, R^(1′), R³, R^(4′), and R⁵ is as defined below anddescribed in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula IV:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y,Ring A, L¹, R³, R⁴, and R⁵ is as defined below and described inembodiments herein, both singly and in combination.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 n electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, AH quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms“heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘); —SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●)—(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of RJ,taken together with their intervening atom(s) form an unsubstituted3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of RJ are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a warhead moiety, R¹, of a provided compound comprises oneor more deuterium atoms. In certain embodiments, Ring B of a providedcompound may be substituted with one or more deuterium atoms.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits TYK2 with measurable affinity. In certainembodiments, an inhibitor has an IC₅₀ and/or binding constant of lessthan about 50 μM, less than about 1 μM, less than about 500 nM, lessthan about 100 nM, less than about 10 nM, or less than about 1 nM.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 44, 2596-99 and Sun et al. BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in a TYK2 protein kinase activitybetween a sample comprising a compound of the present invention, orcomposition thereof, and a TYK2 protein kinase, and an equivalent samplecomprising an TYK2 protein kinase, in the absence of said compound, orcomposition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of X and Y is independently ═C(R⁶)— or ═N—, provided that X and    Y are not simultaneously ═C(R⁶)—;-   Ring A is phenyl; a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur; a 3-6 membered saturated or partially unsaturated    heterocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; or a 4-6 membered saturated or    partially unsaturated carbocyclic ring; wherein Ring A is    substituted with m instances of R⁷;-   each of R¹ and R^(1′) is independently hydrogen, —R², halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R; or    -   R¹ and R^(1′) are taken together to form an oxo group or with        their intervening atoms to form an optionally substituted 3-7        membered spiro-fused ring having 0-2 heteroatoms independently        selected from nitrogen, oxygen, and sulfur;-   each R² is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   R³ is a group selected from C₁₋₆ alkyl, phenyl, a 3-7 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    saturated or partially unsaturated heterocyclic ring having 1-2    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; wherein R³    is substituted with n instances of R⁸;-   R⁴ is hydrogen or optionally substituted C₁₋₆ aliphatic; or    -   R⁴ and one instance of R⁷ are taken together with their        intervening atoms to form a 5-6 membered partially unsaturated        or aromatic ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen and sulfur;-   R^(5′) is an 8-10 membered saturated or partially unsaturated    heterocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; wherein R⁵ is substituted with p    instances of R⁹;-   each instance of R⁶, R⁷, R⁸, R¹⁰, and R¹¹ is independently —R²,    halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   each instance of R⁹ is independently oxo, C₁₋₆ hydroxyaliphatic,    —R², halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   L¹ is a covalent bond or a C₁₋₆ bivalent saturated or unsaturated,    straight or branched hydrocarbon chain wherein one or two methylene    units of the chain are optionally and independently replaced by    —C(R¹⁰)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—,    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; or    -   L¹ and one instance of R⁷ are taken together with their        intervening atoms to form a 5-10 membered partially unsaturated        or aromatic ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen and sulfur; wherein said ring is        substituted by q instances of R¹¹; and R⁵ is attached to any        position of the ring formed by L¹ and R⁷;-   m is 0-4;-   n is 0-4;-   p is 0-6;-   q is 0-4; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur.

In certain embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of X and Y is independently ═C(R⁶)— or ═N—, provided that X and    Y are not simultaneously ═C(R⁶)—;-   Ring A is phenyl; a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur; a 3-6 membered saturated or partially unsaturated    heterocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; or a 4-6 membered saturated or    partially unsaturated carbocyclic ring; wherein Ring A is    substituted with m instances of R⁷;-   each of R¹ and R^(1′) is independently hydrogen, —R², halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R; or    -   R¹ and R^(1′) are taken together to form an oxo group or with        their intervening atoms to form an optionally substituted 3-7        membered spiro-fused ring having 0-2 heteroatoms independently        selected from nitrogen, oxygen, and sulfur;-   each R² is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   R³ is a group selected from C₁₋₆ alkyl, phenyl, a 3-7 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    saturated or partially unsaturated heterocyclic ring having 1-2    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; wherein R³    is substituted with n instances of R⁸;-   R⁴ is hydrogen or optionally substituted C₁₋₆ aliphatic; or    -   R⁴ and one instance of R⁷ are taken together with their        intervening atoms to form a 5-6 membered partially unsaturated        or aromatic ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen and sulfur;-   R⁵ is a group selected from hydrogen, halogen, —CN, —NO₂, —OR, —SR,    —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, —N(R)S(O)₂R, phenyl, a 3-10 membered saturated or    partially unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; wherein R⁵ is    substituted with p instances of R⁹;-   each instance of R⁶, R⁷, R⁸, R¹⁰, and R¹¹ is independently —R²,    halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   each instance of R⁹ is independently oxo, C₁₋₆ hydroxyaliphatic,    —R², halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   L^(1′) is a C₁₋₆ bivalent saturated or unsaturated, straight or    branched hydrocarbon chain wherein at least one methylene unit of    the chain is replaced by —C(R¹⁰)₂—; and one or two additional    methylene units of the chain are optionally and independently    replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—,    —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—;    or    -   L^(1′) and one instance of R⁷ are taken together with their        intervening atoms to form a 5-10 membered partially unsaturated        or aromatic ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen and sulfur; wherein said ring is        substituted by q instances of R¹¹; and R⁵ is attached to any        position of the ring formed by L^(1′) and R⁷;-   m is 0-4;-   n is 0-4;-   p is 0-6;-   q is 0-4; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur.

In certain embodiments, the present invention provides a compound offormula III′:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of X and Y is independently ═C(R⁶)— or ═N—, provided that X and    Y are not simultaneously ═C(R⁶)—;-   Ring A is phenyl; a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur; a 3-6 membered saturated or partially unsaturated    heterocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; or a 4-6 membered saturated or    partially unsaturated carbocyclic ring; wherein Ring A is    substituted with m instances of R⁷;-   each of R¹ and R^(1′) is independently hydrogen, —R², halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R; or    -   R¹ and R^(1′) are taken together to form an oxo group or with        their intervening atoms to form an optionally substituted 3-7        membered spiro-fused ring having 0-2 heteroatoms independently        selected from nitrogen, oxygen, and sulfur;-   each R² is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   R³ is a group selected from C₁₋₆ alkyl, phenyl, a 3-7 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    saturated or partially unsaturated heterocyclic ring having 1-2    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; wherein R³    is substituted with n instances of R⁸;-   R^(4′) and one instance of R⁷ are taken together with their    intervening atoms to form a 5-6 membered partially unsaturated or    aromatic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen and sulfur;-   R⁵ is a group selected from halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,    —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,    —N(R)S(O)₂R, phenyl, a 3-10 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; wherein R⁵ is substituted with p    instances of R⁹;-   each instance of R⁶, R⁷, R⁸, R¹⁰, and R¹¹ is independently —R²,    halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   each instance of R⁹ is independently oxo, C₁₋₆ hydroxyaliphatic,    —R², halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   L¹ is a covalent bond or a C₁₋₆ bivalent saturated or unsaturated,    straight or branched hydrocarbon chain wherein one or two methylene    units of the chain are optionally and independently replaced by    —C(R¹⁰)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—,    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; or    -   L¹ and one instance of R⁷ are taken together with their        intervening atoms to form a 5-10 membered partially unsaturated        or aromatic ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen and sulfur; wherein said ring is        substituted by q instances of R¹¹; and R⁵ is attached to any        position of the ring formed by L¹ and R⁷;-   L² is a C₂₋₆ bivalent saturated or unsaturated, straight or branched    hydrocarbon chain wherein at least one methylene unit is replaced by    —N(R⁴)—; and one or two additional methylene units of the chain are    optionally and independently replaced by —C(R¹⁰)₂—, —N(R)—,    —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—,    —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; or-   L² is —N(R^(4′))—;-   m is 0-4;-   n is 0-4;-   p is 0-6;-   q is 0-4; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur.

In certain embodiments, the present invention provides a compound offormula of formula III′ wherein L² is —N(R⁴)—, thereby forming acompound of formula III:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y,Ring A, R¹, R^(1′), L¹, R³, R⁴, R^(4′), R⁵, is as defined above anddescribed in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula IV:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of X and Y is independently ═C(R⁶)— or ═N—, provided that X and    Y are not simultaneously ═C(R⁶)—;-   Ring A is phenyl; a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur; a 3-6 membered saturated or partially unsaturated    heterocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; or a 4-6 membered saturated or    partially unsaturated carbocyclic ring; wherein Ring A is    substituted with m instances of R⁷;-   each R² is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   R³ is a group selected from C₁₋₆ alkyl, phenyl, a 3-7 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    saturated or partially unsaturated heterocyclic ring having 1-2    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; wherein R³    is substituted with n instances of R⁸;-   R⁴ is hydrogen or optionally substituted C₁₋₆ aliphatic; or    -   R⁴ and one instance of R⁷ are taken together with their        intervening atoms to form a 5-6 membered partially unsaturated        or aromatic ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen and sulfur;-   R⁵ is a group selected from halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,    —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,    —N(R)S(O)₂R, phenyl, a 3-10 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; wherein R⁵ is substituted with p    instances of R⁹;-   each instance of R⁶, R⁷, R⁸, R¹⁰, and R¹¹ is independently —R²,    halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   each instance of R⁹ is independently oxo, C₁₋₆ hydroxyaliphatic,    —R², halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   L¹ is a covalent bond or a C₁₋₆ bivalent saturated or unsaturated,    straight or branched hydrocarbon chain wherein one or two methylene    units of the chain are optionally and independently replaced by    —C(R¹⁰)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—,    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; or    -   L¹ and one instance of R⁷ are taken together with their        intervening atoms to form a 5-10 membered partially unsaturated        or aromatic ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen and sulfur; wherein said ring is        substituted by q instances of R¹¹; and R⁵ is attached to any        position of the ring formed by L¹ and R⁷;-   m is 0-4;-   n is 0-4;-   p is 0-6;-   q is 0-4; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur.

As defined generally above, each of X and Y is ═C(R⁶)— or ═N—, providedthat X and Y are not simultaneously ═C(R⁶)—. In some embodiments, both Xand Y are ═N—. In some embodiments, X is ═N—, and Y is ═C(R⁶)—. In someembodiments, X is ═C(R⁶)—, and Y is ═N—.

In some embodiments, each of X and Y is independently ═C(R⁶)—, ═N—, or═N⁺(→O⁻)—, provided that X and Y are not simultaneously ═C(R⁶)—. In someembodiments, X is ═C(R⁶)—, and Y is ═N⁺(→O⁻)—.

As defined generally above, Ring A is phenyl; a 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; or a 3-6 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; wherein Ring A is substituted with minstances of R⁷.

In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a5-6 membered heteroaryl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Ring A is a 5-membered heteroarylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, Ring A is a 6-membered heteroaryl having1-4 nitrogens. In some embodiments, Ring A is pyridyl. In someembodiments, Ring A is pyrazolyl.

One of skill in the art will appreciate that a when Ring A is a 5-6membered heteroaryl ring, multiple regioisomers are possible. Unlessotherwise stated, all regioisomers are intended to be encompassed. Insome embodiments, Ring A is 2-pyridyl. In some embodiments, Ring A is3-pyridyl. In some embodiments, Ring A is 3-pyrazolyl. In someembodiments, Ring A is 4-pyrazolyl.

Likewise, when Ring A is phenyl, multiple attachment points arepossible. In some embodiments, when Ring A is phenyl, L¹ is para to thepoint of attachment to the rest of the molecule. In some embodiments, L¹is meta to the point of attachment to the rest of the molecule. In someembodiments, L¹ is ortho to the point of attachment to the rest of themolecule. In some embodiments, when Ring A is phenyl, and -L¹R⁵ takentogether is C₁₋₆ aliphatic, said -L¹R⁵ group is para to the point ofattachment to the rest of the molecule.

As defined generally above, the n group of formula I is 0-4. In someembodiments, n is 0. In some embodiments, n is 1-4. In certainembodiments, n is 1. In some embodiments, n is 2. In certainembodiments, n is 3. In certain embodiments, n is 4.

As defined generally above, each of R¹ and R^(1′) is independentlyhydrogen, —R², halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂,—S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R; or R¹ and R^(1′)are taken together with their intervening atoms to form an optionallysubstituted 4-7 membered spiro-fused ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In certain embodiments, each of R¹ and R^(1′) are hydrogen. In someembodiments, each of R¹ and R^(1′) is independently —R², halogen, —CN,—NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, or —N(R)S(O)₂R. In certain embodiments, each of R¹ andR^(1′) are methyl. In some embodiments, one of R¹ and R^(1′) is methyl,and the other is hydrogen. In some embodiments, R¹ and R^(1′) are takentogether with their intervening atoms to form an optionally substituted3-7 membered spiro-fused ring having 0-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ andR^(1′) are taken together with their intervening atoms to form anoptionally substituted 3-7 membered spiro-fused carbocyclic ring. Insome embodiments, R¹ and R^(1′) are taken together with theirintervening atoms to form an optionally substituted spirocycloprpylring. In some embodiments, R¹ and R^(1′) are taken together with theirintervening atoms to form an optionally substituted 3-7 memberedspiro-fused heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

As defined generally above, R³ is a group selected from C₁₋₆ alkyl,phenyl, a 3-7 membered saturated or partially saturated carbocyclicring, a 3-7 membered saturated or partially unsaturated heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein R³ is substituted with n instances of R⁸.

In some embodiments, R³ is a group selected from phenyl, a 3-7 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R³ is phenyl. In some embodiments, when X is ═N—,R³ is phenyl.

In some embodiments, R³ is a 3-7 membered saturated or partiallyunsaturated carbocyclic ring. In some embodiments, R³ is a 3-7 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R³ is a 5-6 membered saturated heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments R³ is pyrrolidinyl. In some embodiments, R³is piperidinyl.

In some embodiments, R³ is a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R³ is pyridinyl. In some embodiments, R³ is a C₃₋₆saturated or partially unsaturated carbocyclic ring. Exemplary R³ groupsinclude those depicted in Table 1.

As defined generally above, R⁴ is hydrogen or optionally substitutedC₁₋₆ aliphatic. In some embodiments, R⁴ is hydrogen. In someembodiments, R⁴ is optionally substituted C₁₋₆ aliphatic. In someembodiments, R⁴ is unsubstituted C₁₋₆ aliphatic. In some embodiments, R⁴is optionally substituted C₁₋₆ alkyl. In some embodiments, R⁴ isoptionally substituted C₃₋₆ cycloalkyl.

As defined generally above, L¹ is a covalent bond or a C₁₋₆ bivalentsaturated or unsaturated, straight or branched hydrocarbon chain whereinone or two methylene units of the chain are optionally and independentlyreplaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—,—O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; or L¹ and oneinstance of R⁷ are taken together with their intervening atoms to form a5-6 membered partially unsaturated or aromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen and sulfur;wherein said ring is substituted by q instances of R¹¹; and R⁵ isattached to any position of the ring formed by L¹ and R⁷.

In some embodiments, L¹ is a covalent bond or a C₁₋₆ bivalent saturatedor unsaturated, straight or branched hydrocarbon chain wherein one ortwo methylene units of the chain are optionally and independentlyreplaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—,—O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—.

In some embodiments, L¹ and one instance of R⁷ are taken together withtheir intervening atoms to form a 5-6 membered partially unsaturated oraromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen and sulfur; wherein said ring is substituted by qinstances of R¹¹; and R⁵ is attached to any position of the ring formedby L¹ and R⁷.

In some embodiments, when L¹ is a covalent bond, R⁵ is not unsubstitutedalkyl. In some embodiments, L¹ is a covalent bond. In other embodiments,L¹ is a C₁₋₆ bivalent hydrocarbon chain wherein one or two methyleneunits of the chain are optionally and independently replaced by —N(R)—,—N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—,—C(O)O—, —S—, —S(O)— or —S(O)₂—. In some embodiments, L¹ is a C₂₋₆bivalent branched hydrocarbon chain. In some embodiments, L¹ is a C₃₋₆bivalent branched alkylene chain.

In some embodiments, L¹ is a C₂ bivalent hydrocarbon chain wherein onemethylene unit of the chain is replaced by —C(O)—. In some embodiments,L¹ is —CH₂C(O)— (wherein the carbonyl is adjacent to R⁵). In someembodiments, L¹ is —C(O)—. In some embodiments, L¹ is a covalent bond or—C(O)—. Exemplary L¹ groups include those depicted in Table 1.

In some embodiments, L¹ is a covalent bond or a C₁₋₆ bivalent saturatedor unsaturated, straight or branched hydrocarbon chain wherein one ortwo methylene units of the chain are optionally and independentlyreplaced by —C(R¹⁰)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—,—S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; orL¹ and one instance of R⁷ are taken together with their interveningatoms to form a 5-10 membered partially unsaturated or aromatic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen,sulfur, and boron; wherein said ring is substituted by q instances ofR¹¹; and R⁵ is attached to any position of the ring formed by L¹ and R⁷.In some embodiments, L¹ and one instance of R⁷ are taken together withtheir intervening atoms to form a 5-10 membered partially unsaturated oraromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, sulfur, and boron; wherein said ring is substituted byq instances of R¹¹; and R⁵ is attached to any position of the ringformed by L¹ and R⁷.

As defined generally above, L^(1′) is a C₁₋₆ bivalent saturated orunsaturated, straight or branched hydrocarbon chain wherein at least onemethylene unit of the chain is replaced by —C(R¹⁰)₂—; and one or twoadditional methylene units of the chain are optionally and independentlyreplaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—,—O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; or L¹ and oneinstance of R⁷ are taken together with their intervening atoms to form a5-10 membered partially unsaturated or aromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen and sulfur;wherein said ring is substituted by q instances of R¹¹; and R⁵ isattached to any position of the ring formed by L¹ and R⁷.

In some embodiments, L^(1′) is —C(R¹⁰)₂—. In some embodiments, L^(1′)and one instance of R⁷ are taken together with their intervening atomsto form a 5-10 membered partially unsaturated or aromatic ring having1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;wherein said ring is substituted by q instances of R¹¹; and R⁵ isattached to any position of the ring formed by L^(1′) and R⁷. In someembodiments, L^(1′) and one instance of R⁷ are taken together with theirintervening atoms to form a 5-6 membered partially unsaturated oraromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen and sulfur; wherein said ring is substituted by qinstances of R¹¹; and R⁵ is attached to any position of the ring formedby L¹ and R⁷. In some embodiments, L^(1′) and one instance of R⁷ aretaken together with their intervening atoms to form a 7-10 memberedpartially unsaturated or aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen and sulfur; wherein saidring is substituted by q instances of R¹¹; and R⁵ is attached to anyposition of the ring formed by L¹ and R⁷. Exemplary L¹ groups aredepicted in Table 1.

In some embodiments, L^(1′) is a C₁₋₆ bivalent saturated or unsaturated,straight or branched hydrocarbon chain wherein at least one methyleneunit of the chain is replaced by —C(R¹⁰)₂—; and one or two additionalmethylene units of the chain are optionally and independently replacedby —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—,—C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; or L^(1′) and oneinstance of R⁷ are taken together with their intervening atoms to form a5-10 membered partially unsaturated or aromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, sulfur, andboron; wherein said ring is substituted by q instances of R¹¹; and R⁵ isattached to any position of the ring formed by L^(1′) and R⁷. In someembodiments, L^(1′) and one instance of R⁷ are taken together with theirintervening atoms to form a 5-10 membered partially unsaturated oraromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, sulfur, and boron; wherein said ring is substituted byq instances of R¹¹; and R⁵ is attached to any position of the ringformed by L^(1′) and R⁷.

As defined generally above, R⁵ is a group selected from halogen, —CN,—NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, —N(R)S(O)₂R, phenyl, 3-7 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; wherein R⁵ is substituted with p instances of R⁹.

In some embodiments, R⁵ is selected from —OR, —NR₂, and a 3-10 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R⁵ is selected from —OH, —OEt, —NH₂, NHEt, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,oxetanyl, tetrahydrothiopyranyl, and tetrahydrofuranyl. In someembodiments, R⁵ is —OR. In some embodiments, R⁵ is —NR₂. In someembodiments, R⁵ is —NHEt or —NH/Pr. Exemplary R⁵ groups include thosedepicted in Table 1.

In some embodiments, R⁵ is a 4-10 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R⁵ isan 4-membered saturated heterocyclic ring having 1 heteroatom selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, R⁵ is an5-membered saturated or partially unsaturated heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R⁵ is an 6-membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R⁵ isan 7-membered saturated or partially unsaturated heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R⁵ is an 8-membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R⁵ isan 9-membered saturated or partially unsaturated heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R⁵ is an 10-membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R⁵ isan 8-membered saturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁵ is an 9-membered saturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R⁵ is an 10-membered saturated heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R⁵ is an 7-10 membered saturated orpartially unsaturated spirocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R⁵ is an 7-10 membered saturated or partiallyunsaturated fused bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R⁵ is a group selected from halogen, —CN, —NO₂,—OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)S(O)₂R, phenyl, 3-14 membered saturated or partially unsaturatedheterocyclic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; wherein R⁵ is substituted with p instances of R⁹. In someembodiments, R⁵ is a group selected from a 3-14 membered saturated orpartially unsaturated heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, and 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, R⁵ is a 3-14membered saturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R⁵ is a group selected from a 10-14 membered saturatedor partially unsaturated heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁵ is a group selected from a 10-14 membered saturated orpartially unsaturated bicyclic heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁵ is a group selected from a 10-14 membered saturated orpartially unsaturated tricyclic heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁵ is a group selected from a 10-14 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁵ is a group selected from a 10-14 membered saturated orpartially unsaturated bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁵ is a group selected from a 10-14 membered saturated orpartially unsaturated tricyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(5′) is an 8-10 membered saturated or partiallyunsaturated bridged bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

As defined generally above, R^(5′) is an 8-10 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein R⁵ issubstituted with p instances of R⁹. In some embodiments, R⁵ is an8-membered saturated or partially unsaturated heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R⁵ is an 9-membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R⁵ isan 10-membered saturated or partially unsaturated heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R⁵ is an 8-membered saturated heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, R⁵ is an 9-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R⁵ is an 10-memberedsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R⁵ isan 8-10 membered saturated or partially unsaturated spirocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R⁵ is an 8-10membered saturated or partially unsaturated fused bicyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, R⁵ is an 8-10 memberedsaturated or partially unsaturated bridged bicyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

In some embodiments, R⁵ is an 8-14 membered saturated or partiallyunsaturated heterocyclic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; wherein R⁵ is substitutedwith p instances of R⁹. In some embodiments, R⁵ is an 8-12 memberedsaturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R⁵ is an 10-14 membered saturated or partiallyunsaturated heterocyclic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R⁵ isan 8-14 membered saturated or partially unsaturated heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R⁵ is an 8-14 membered saturated orpartially unsaturated bicyclic heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁵ is an 8-14 membered saturated or partially unsaturatedtricyclic heterocyclic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

As defined generally above each instance of R⁶ is independently —R²,halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R. In some embodiments R⁶ ishalogen or —CN. In some embodiments R⁶ is halogen. In some embodiments,R⁶ is fluoro. In some embodiments, R⁶ is —CN.

In some embodiments, R⁶ is hydrogen, —R², halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R. In some embodiments, R⁶ is hydrogen. In some embodimentsR⁶ is halogen or —CN. In some embodiments R⁶ is halogen. In someembodiments, R⁶ is fluoro. In some embodiments, R⁶ is —CN.

As defined generally above, each instance of R⁷ is —R², halogen, —CN,—NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, or —N(R)S(O)₂R.

In some embodiments, R⁷ is oxo, —R², halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,—OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or—N(R)S(O)₂R.

As defined generally above, each instance of R⁸ is independently —R²,halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R. In some embodiments, R⁸ is ahalogen. In some embodiments, R⁸ is fluorine. In some embodiments, R⁸ ischlorine. In some embodiments, R⁸ is optionally substituted C₁₋₆aliphatic. In some embodiments, R⁸ is C₁₋₆ alkyl. In some embodiments,R⁸ is methyl. In some embodiments, R⁸ is alkyl substituted by one ormore halogens. In some embodiments, R⁸ is CF₃. In some embodiments, eachR⁸ is a halogen. In some embodiments, each R⁸ is fluorine, chlorine,methyl, or CF₃.

In some embodiments, R⁸ is oxo, —R², halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,—OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or—N(R)S(O)₂R.

One of ordinary skill in the art will appreciate that an R⁸ substituenton a saturated carbon of R³ forms a chiral center. In some embodiments,that chiral center is in the (R) configuration. In other embodiments,that chiral center is in the (S) configuration.

As defined generally above, each instance of R⁹ is independently oxo,C₁₋₆ hydroxyaliphatic, —R², halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R,—S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R,—OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R.

In some embodiments, R⁸ is oxo, —R², halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,—OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or—N(R)S(O)₂R.

In some embodiments, R⁹ is oxo. In some embodiments, R⁹ is —R². In someembodiments, R⁹ is optionally substituted C₁₋₆ aliphatic. In someembodiments, R⁹ is C₁₋₆ hydroxyaliphatic. In some embodiments, R⁹ ishydroxymethyl. In some embodiments, R⁹ is hydroxyethyl. In someembodiments, R⁹ is hydroxy cyclobutyl. In some embodiments, R⁹ ishydroxy cyclobutyl. In some embodiments, R⁹ is N,N-dimethylaminoethyl.In some embodiments, R⁹ is a 3-7 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R⁹ isselected from —OH, —OEt, —NH₂, NHEt, aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, oxetanyl,tetrahydrothiopyranyl, and tetrahydrofuranyl. In some embodiments, whenL¹ is absent, at least one R⁹ is oxo.

As defined generally above, each instance of R¹⁰ is independently —R²,halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R.

In some embodiments, R¹⁰ is oxo, —R², halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

As defined generally above, m is 0-4. In some embodiments, m is 0. Insome embodiments, m is 1-4. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

As defined generally above, n is 0-4. In some embodiments, n is 0. Insome embodiments, n is 1-4. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4. In some embodiments, n is 0-1. In some embodiments, n is 0-2. Insome embodiments, n is 0-3.

As defined generally above, p is 0-6. In some embodiments, p is 0. Insome embodiments, p is 1-6. In some embodiments, p is 1. In someembodiments, p is 2. In some embodiments, p is 3. In some embodiments, pis 1-3. In some embodiments, p is 4. In some embodiments, p is 5. Insome embodiments, p is 6.

As defined generally above, q is 0-4. In some embodiments, q is 0. Insome embodiments, q is 1-4. In some embodiments, q is 1. In someembodiments, q is 2. In some embodiments, q is 3. In some embodiments, qis 4. In some embodiments, q is 0-1. In some embodiments, q is 0-2. Insome embodiments, q is 0-3.

In certain embodiments, the present invention provides a compound offormula I, wherein when X is ═N—, R³ is phenyl.

In certain embodiments, the present invention provides a compound offormulas I, II, or III, wherein R¹ and R^(1′) are each hydrogen, therebyforming a compound of formulas I-a, II-a, or III-a respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y,Ring A, L¹, L^(1′), R³, R⁴, R^(4′), R⁵, and R^(5′) is as defined aboveand described in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormulas I, II, III, or IV wherein X is ═N— and Y is ═C(R⁶)—; therebyforming a compound of formula I-b, II-b, III-b, or IV-b respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, L^(1′), R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), and R⁶ is as definedabove and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormulas I, II, III, or IV wherein X is ═C(R⁶)—; and Y is ═N—, therebyforming a compound of formula I-c, II-c, III-c, or IV-c respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, L^(1′), R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), and R⁶ is as definedabove and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormulas I, II, III, or IV wherein X is ═C(R⁶)—; and Y is ═N⁺(→O⁻)—,thereby forming a compound of formula I-c-i, II-c-i, III-c-i, or IV-c-irespectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, L^(1′), R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), and R⁶ is as definedabove and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormulas I, II, III, or IV wherein X and Y are each ═N—, thereby forminga compound of formula I-d, II-d, III-d, or IV-d respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, L^(1′), R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), and R⁶ is as definedabove and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound of anyone of formulas I-b, I-c, II-b, II-c, III-b, III-c, IV-b, or IV-cwherein R⁶ is hydrogen. In some embodiments, the present inventionprovides a compound of any one of formulas I-b, I-c, II-b, II-c, III-b,III-c, IV-b, or IV-c wherein R⁶ is halogen. In some embodiments, thepresent invention provides a compound of any one of formulas I-b, I-c,II-b, II-c, III-b, III-c, IV-b, or IV-c wherein R⁶ is fluoro. In someembodiments, the present invention provides a compound of any one offormulas I-b, I-c, II-b, II-c, III-b, III-c, IV-b, or IV-c wherein R⁶ is—CN.

In certain embodiments, the present invention provides a compound of anyone of formulas I, II, III, IV, I-a, II-a, III-a, I-b, II-b, III-b,IV-b, I-c, II-c, III-c, IV-c, I-d, II-d, III-d, or IV-d, wherein Ring Ais phenyl, pyridin-2-yl, pyridine-3-yl, pyrazinyl, pyridazinyl, orpyrazol-4-yl.

In certain embodiments, the present invention provides a compound of oneof formulas I, II, III, or IV wherein Ring A is phenyl, and L¹ is parato —N(R⁴)— or —N(R^(4′))—, thereby forming a compound of one of formulasI-e, II-e, III-e, and IV-e respectively:

or a pharmaceutically acceptable salt thereof, wherein each of, X, Y,L¹, L^(1′), R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), R⁷, and m is asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound of oneof formulas I, II, III, or IV wherein Ring A is pyridin-2-yl, and L¹ ispara to —N(R⁴)— or —N(R^(4′))—, thereby forming a compound of one offormulas I-f, II-f, III-f, and IV-f respectively:

or a pharmaceutically acceptable salt thereof, wherein each of, X, Y,L¹, L^(1′), R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), R⁷, and m is asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound of oneof formulas I, II, III, or IV wherein Ring A is pyridine-3-yl, and L¹ ispara to —N(R⁴)— or —N(R^(4′))—, thereby forming a compound of one offormulas I-g, II-g, III-g, and IV-g respectively:

or a pharmaceutically acceptable salt thereof, wherein each of, X, Y,L¹, L^(1′), R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), R⁷, and m is asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound of oneof formulas I, II, III, or IV wherein Ring A is pyridazinyl, and L¹ ispara to —N(R⁴)— or —N(R^(4′))—, thereby forming a compound of one offormulas I-h, II-h, III-h, and IV-h respectively:

or a pharmaceutically acceptable salt thereof, wherein each of, X, Y,L¹, L^(1′), R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), R⁷, and m is asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound of oneof formulas I, II, III, or IV wherein Ring A is pyrazinyl, and L¹ ispara to —N(R⁴)— or —N(R^(4′))—, thereby forming a compound of one offormulas I-i, II-i, III-i, and IV-i respectively:

or a pharmaceutically acceptable salt thereof, wherein each of, X, Y,L¹, L^(1′), R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), R⁷, and m is asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound of oneof formulas I, II, III, or IV wherein Ring A is pyrazol-4-yl, and L¹ ispara to —N(R⁴)— or —N(R^(4′))—, thereby forming a compound of one offormulas I-j, II-j, III-j, and IV-j respectively:

or a pharmaceutically acceptable salt thereof, wherein each of, X, Y,L¹, L^(1′), R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), R⁷, and m is asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound of oneof formulas I, II, III, or IV, wherein R³ is phenyl, pyrrolidinyl, orpiperidinyl. In certain embodiments, the present invention provides acompound of one of formulas I, II, III, or IV, wherein R³ is phenyl,thereby forming a compound of formula I-k, II-k, III-k, or IV-k,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y,Ring A, L¹, L^(1′), R¹, R^(1′), R⁴, R^(4′), R⁵, R^(5′), R⁸, and n is asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound of oneof formulas I, II, III, or IV, or a pharmaceutically acceptable saltthereof, wherein n is 1-3, and at least one R⁸ substituent is ortho tothe point of attachment. In certain embodiments, the present inventionprovides a compound of one of formulas I, II, III, or IV, or apharmaceutically acceptable salt thereof, wherein n is 1. In certainembodiments, the present invention provides a compound of one offormulas I, II, III, or IV, or a pharmaceutically acceptable saltthereof, wherein n is 2. In certain embodiments, the present inventionprovides a compound of one of formulas I, II, III, or IV, or apharmaceutically acceptable salt thereof, wherein n is 2, and at leastone R⁸ is halogen. In certain embodiments, the present inventionprovides a compound of one of formulas I, II, III, or IV, or apharmaceutically acceptable salt thereof, wherein n is 2, and at leastone R⁸ is fluoro.

In certain embodiments, the present invention provides a compound of oneof formulas I-k, II-k, III-k, or IV-k, wherein n is 2 and each R⁸ isfluoro, thereby forming a compound of formula I-l, II-l, III-l, or IV-l,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y,Ring A, L¹, L^(1′), R¹, R^(1′), R⁴, R^(4′), R⁵, and R^(5′), is asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound of oneof formulas I, III, or IV, wherein L¹ is a covalent bond or —C(O)—,thereby forming a compound of formula I-m, III-m, or IV-m, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y,Ring A, R¹, R^(1′), R³, R⁴, R^(4′), R⁵, and R^(5′) is as defined aboveand described in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound of oneof formulas I, III, or IV, wherein L¹ is —C(O)—, thereby forming acompound of formula I-n, III-n, or IV-n, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y,Ring A, R¹, R^(1′), R³, R⁴, R^(4′), R⁵, and R^(5′) is as defined aboveand described in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound of oneof formulas I-n, III-n, or IV-n, wherein X is ═C(R⁶)— and Y is ═N—,thereby forming a compound of formula I-o, III-o, or IV-o, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), and R⁶ is as defined above anddescribed in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound of oneof formulas I-m, III-m, or IV-m, wherein X is ═C(R⁶)— and Y is ═N—,thereby forming a compound of formula I-p, III-p, or IV-p, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,R¹, R^(1′), R³, R⁴, R^(4′), R⁵, R^(5′), and R⁶ is as defined above anddescribed in embodiments herein, both singly and in combination.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Exemplary Compounds Com- pound # Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

In some embodiments, the method employs a compound set forth in Table 1,above, or a pharmaceutically acceptable salt thereof. In someembodiments, the present invention provides a compound set forth inTable 1, above, or a pharmaceutically acceptable salt thereof. In someembodiments, the present invention provides a pharmaceutical compositioncomprising a compound set forth in Table 1 above, or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier, excipient, or diluent.

Without wishing to be bound by any particular theory, it is believedthat proximity of an inhibitor compound, or pendant moiety of aninhibitor compound, to the water of interest facilitates displacement ordisruption of that water by the inhibitor compound, or pendant moiety ofan inhibitor compound. In some embodiments, a water molecule displacedor disrupted by an inhibitor compound, or pendant moiety of an inhibitorcompound, is an unstable water molecule.

In certain embodiments, the method employs a complex comprising TYK2 andan inhibitor, wherein at least one unstable water of TYK2 is displacedor disrupted by the inhibitor. In some embodiments, at least twounstable waters selected are displaced or disrupted by the inhibitor.

4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit a TYK2 protein kinase, or amutant thereof, in a biological sample or in a patient. In certainembodiments, the amount of compound in compositions of this invention issuch that is effective to measurably inhibit a TYK2 protein kinase, or amutant thereof, in a biological sample or in a patient. In certainembodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof a TYK2 protein kinase, or a mutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of kinase activity of one or more enzymes. In someembodiments the kinase inhibited by the compounds and methods of theinvention is TYK2

TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs)family of protein kinases. The mammalian JAK family consists of fourmembers, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, areintegral to cytokine signaling. TYK2 associates with the cytoplasmicdomain of type I and type II cytokine receptors, as well as interferontypes I and III receptors, and is activated by those receptors uponcytokine binding. Cytokines implicated in TYK2 activation includeinterferons (e.g. IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, andIFN-ζ (also known as limitin), and interleukins (e.g. IL-4, IL-6, IL-10,IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliaryneurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, andLIF). Velasquez et al., “A protein kinase in the interferon α/βsignaling pathway,” Cell (1992) 70:313; Stahl et al., “Association andactivation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptorcomponents,” Science (1994) 263:92; Finbloom et al., “IL-10 induces thetyrosine phosphorylation of Tyk2 and Jak1 and the differential assemblyof Stat1 and Stat3 complexes in human T cells and monocytes,” J.Immunol. (1995) 155:1079; Bacon et al., “Interleukin 12 (IL-12) inducestyrosine phosphorylation of Jak2 and Tyk2: differential use of Janusfamily kinases by IL-2 and IL-12,” J. Exp. Med. (1995) 181:399; Welhamet al., “Interleukin-13 signal transduction in lymphohemopoietic cells:similarities and differences in signal transduction with interleukin-4and insulin,” J. Biol. Chem. (1995) 270:12286; Parham et al., “Areceptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1and a novel cytokine receptor subunit, IL-23R,” J. Immunol. (2002)168:5699. The activated TYK2 then goes on to phosphorylate furthersignaling proteins such as members of the STAT family, including STAT1,STAT2, STAT4, and STAT6.

TYK2 activation by IL-23, has been linked to inflammatory bowel disease(IBD), Crohn's disease, and ulcerative colitis. Duerr et al., “AGenome-Wide Association Study Identifies IL23R as an Inflammatory BowelDisease Gene,” Science (2006) 314:1461-1463. As the downstream effectorof IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis,and Beliefs disease. Cho et al., “Genomics and the multifactorial natureof human auto-immune disease,” N. Engl. J. Med (2011) 365:1612-1623;Cortes et al., “Identification of multiple risk variants for ankylosingspondylitis through high-density genotyping of immune-related loci,”Nat. Genet. (2013) 45(7):730-738; Remmers et al., “Genome-wideassociation study identifies variants in the MHC class I, IL10, andIL23R-IL12RB2 regions associated with Beliefs disease,” Nat. Genet.(2010) 42:698-702. A genome-wide association study of 2,622 individualswith psoriasis identified associations between disease susceptibilityand TYK2. Strange et al., “A genome-wide association study identifiesnew psoriasis susceptibility loci and an interaction between HLA-C andERAP1,” Nat. Genet. (2010) 42:985-992. Knockout or tyrphostin inhibitionof TYK2 significantly reduces both IL-23 and IL-22-induced dermatitis.Ishizaki et al., “Tyk2 is a therapeutic target for psoriasis-like skininflammation,” Inti. Immunol. (2013), doi: 10.1093/intimm/dxt062.

TYK2 also plays a role in respiratory diseases such as asthma, chronicobstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis.Goblet cell hyperplasia (GCH) and mucous hypersecretion is mediated byIL-13-induced activation of TYK2, which in turn activates STAT6. Zhanget al., “Docking protein Gab2 regulates mucin expression and goblet cellhyperplasia through TYK2/STAT6 pathway,” FASEB J. (2012) 26:1-11.

Decreased TYK2 activity leads to protection of joints from collagenantibody-induced arthritis, a model of human rheumatoid arthritis.Mechanistically, decreased Tyk2 activity reduced the production ofT_(h)1/T_(h)17-related cytokines and matrix metalloproteases, and otherkey markers of inflammation. Ishizaki et al., “Tyk2 deficiency protectsjoints against destruction in anti-type II collagen antibody-inducedarthritis in mice,” Inti. Immunol. (2011) 23(9):575-582.

TYK2 knockout mice showed complete resistance in experimental autoimmuneencephalomyelitis (EAE, an animal model of multiple sclerosis (MS)),with no infiltration of CD4 T cells in the spinal cord, as compared tocontrols, suggesting that TYK2 is essential to pathogenic CD4-mediateddisease development in MS. Oyamada et al., “Tyrosine Kinase 2 PlaysCritical Roles in the Pathogenic CD4 T Cell Responses for theDevelopment of Experimental Autoimmune Encephalomyelitis,” J. Immunol.(2009) 183:7539-7546. This corroborates earlier studies linkingincreased TYK2 expression with MS susceptibility. Ban et al.,“Replication analysis identifies TYK2 as a multiple sclerosissusceptibility factor,” Eur J. Hum. Genet. (2009) 17:1309-1313. Loss offunction mutation in TYK2, leads to decreased demyelination andincreased remyelination of neurons, further suggesting a role for TYK2inhibitors in the treatment of MS and other CNS demyelination disorders.

TYK2 is the sole signaling messenger common to both IL-12 and IL-23.TYK2 knockout reduced methylated BSA injection-induced footpadthickness, imiquimod-induced psoriasis-like skin inflammation, anddextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid-inducedcolitis in mice.

Joint linkage and association studies of various type I IFN signalinggenes with systemic lupus erythematosus (SLE, an autoimmune disorder),showed a strong, and significant correlation between loss of functionmutations to TYK2 and decreased prevalence of SLE in families withaffected members. Sigurdsson et al., “Polymorphisms in the TyrosineKinase 2 and Interferon Regulatory Factor 5 Genes Are Associated withSystemic Lupis Erythematosus,” Am. J. Hum. Genet. (2005) 76:528-537.Genome-wide association studies of individuals with SLE versus anunaffected cohort showed highly significant correlation between the TYK2locus and SLE. Graham et al., “Association of NCF2, IKZF1, IRF8, IFIH1,and TYK2 with Systemic Lupus Erythematosus,” PLoS Genetics (2011)7(10):e1002341.

TYK2 has been shown to play an important role in maintaining tumorsurveillance and TYK2 knockout mice showed compromised cytotoxic T cellresponse, and accelerated tumor development. However, these effects werelinked to the efficient suppression of natural killer (NK) and cytotoxicT lymphocytes, suggesting that TYK2 inhibitors would be highly suitablefor the treatment of autoimmune disorders or transplant rejection.Although other JAK family members such as JAK3 have similar roles in theimmune system, TYK2 has been suggested as a superior target because ofits involvement in fewer and more closely related signaling pathways,leading to fewer off-target effects. Simma et al. “Identification of anIndispensable Role for Tyrosine Kinase 2 in CTL-Mediated TumorSurveillance,” Cancer Res. (2009) 69:203-211.

However, paradoxically to the decreased tumor surveillance observed bySimma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL)indicate that T-ALL is highly dependent on IL-10 via TYK2 viaSTAT1-mediated signal transduction to maintain cancer cell survivalthrough upregulation of anti-apoptotic protein BCL2. Knockdown of TYK2,but not other JAK family members, reduced cell growth. Specificactivating mutations to TYK2 that promote cancer cell survival includethose to the FERM domain (G36D, S47N, and R425H), the JH2 domain(V731I), and the kinase domain (E957D and R1027H). However, it was alsoidentified that the kinase function of TYK2 is required for increasedcancer cell survival, as TYK2 enzymes featuring kinase-dead mutations(M978Y or M978F) in addition to an activating mutation (E957D) resultedin failure to transform. Sanda et al. “TYK2-STAT1-BCL2 PathwayDependence in T-Cell Acute Lymphoblastic Leukemia,” Cancer Disc. (2013)3(5):564-577.

Thus, selective inhibition of TYK2 has been suggested as a suitabletarget for patients with IL-10 and/or BCL2-addicted tumors, such as 70%of adult T-cell leukemia cases. Fontan et al. “Discovering What MakesSTAT Signaling TYK in T-ALL,” Cancer Disc. (2013) 3:494-496.

TYK2 mediated STAT3 signaling has also been shown to mediate neuronalcell death caused by amyloid-β (Aβ) peptide. Decreased TYK2phosphorylation of STAT3 following Aβ administration lead to decreasedneuronal cell death, and increased phosphorylation of STAT3 has beenobserved in postmorterm brains of Alzheimer's patients. Wan et al.“Tyk/STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death:Implications in Alzheimer's Disease,” J. Neurosci. (2010)30(20):6873-6881.

Inhibition of JAK-STAT signaling pathways is also implicated in hairgrowth, and the reversal of the hair loss associated with alopeciaareata. Xing et al., “Alopecia areata is driven by cytotoxic Tlymphocytes and is reversed by JAK inhibition,” Nat. Med. (2014) 20:1043-1049; Harel et al., “Pharmacologic inhibition of JAK-STAT signalingpromotes hair growth,” Sci. Adv. (2015) 1(9):e1500973.

Accordingly, compounds that inhibit the activity of TYK2 are beneficial,especially those with selectivity over JAK2. Such compounds shoulddeliver a pharmacological response that favorably treats one or more ofthe conditions described herein without the side-effects associated withthe inhibition of JAK2.

Even though TYK2 inhibitors are known in the art, there is a continuingneed to provide novel inhibitors having more effective or advantageouspharmaceutically relevant properties. For example, compounds withincreased activity, selectivity over other JAK kinases (especiallyJAK2), and ADMET (absorption, distribution, metabolism, excretion,and/or toxicity) properties. Thus, in some embodiments, the presentinvention provides inhibitors of TYK2 which show selectivity over JAK2.

The activity of a compound utilized in this invention as an inhibitor ofTYK2, or a mutant thereof, may be assayed in vitro, in vivo or in a cellline. In vitro assays include assays that determine inhibition of eitherthe phosphorylation activity and/or the subsequent functionalconsequences, or ATPase activity of activated TYK2, or a mutant thereof.Alternate in vitro assays quantitate the ability of the inhibitor tobind to TYK2. Inhibitor binding may be measured by radiolabeling theinhibitor prior to binding, isolating the inhibitor/TYK2 complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with TYK2 bound to known radioligands.Representative in vitro and in vivo assays useful in assaying a TYK2inhibitor include those described and disclosed in, e.g., each of whichis herein incorporated by reference in its entirety. Detailed conditionsfor assaying a compound utilized in this invention as an inhibitor ofTYK2, or a mutant thereof, are set forth in the Examples below.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are inhibitors of TYK2 and are therefore useful fortreating one or more disorders associated with activity of TYK2 ormutants thereof. Thus, in certain embodiments, the present inventionprovides a method for treating a TYK2-mediated disorder comprising thestep of administering to a patient in need thereof a compound of thepresent invention, or pharmaceutically acceptable composition thereof.

As used herein, the term “TYK2-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which TYK2 or a mutant thereof is known to play a role.Accordingly, another embodiment of the present invention relates totreating or lessening the severity of one or more diseases in whichTYK2, or a mutant thereof, is known to play a role. Such TYK2-mediateddisorders include but are not limited to autoimmune disorders,inflammatory disorders, proliferative disorders, endocrine disorders,neurological disorders and disorders associated with transplantation.

In some embodiments, the present invention provides a method fortreating one or more disorders, wherein the disorders are selected fromautoimmune disorders, inflammatory disorders, proliferative disorders,endocrine disorders, neurological disorders, and disorders associatedwith transplantation, said method comprising administering to a patientin need thereof, a pharmaceutical composition comprising an effectiveamount of a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the disorder is an autoimmune disorder. In someembodiments the disorder is selected from type 1 diabetes, systemiclupus erythematosus, multiple sclerosis, psoriasis, Behçet's disease,POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatorybowel disease.

In some embodiments, the disorder is an inflammatory disorder. In someembodiments, the inflammatory disorder is rheumatoid arthritis, asthma,chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn'sdisease, ulcerative colitis, inflammatory bowel disease.

In some embodiments, the disorder is a proliferative disorder. In someembodiments, the proliferative disorder is a hematological cancer. Insome embodiments the proliferative disorder is a leukemia. In someembodiments, the leukemia is a T-cell leukemia. In some embodiments theT-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In someembodiments the proliferative disorder is polycythemia vera,myelofibrosis, essential or thrombocytosis.

In some embodiments, the disorder is an endocrine disorder. In someembodiments, the endocrine disorder is polycystic ovary syndrome,Crouzon's syndrome, or type 1 diabetes.

In some embodiments, the disorder is a neurological disorder. In someembodiments, the neurological disorder is Alzheimer's disease.

In some embodiments the proliferative disorder is associated with one ormore activating mutations in TYK2. In some embodiments, the activatingmutation in TYK2 is a mutation to the FERM domain, the JH2 domain, orthe kinase domain. In some embodiments the activating mutation in TYK2is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

In some embodiments, the disorder is associated with transplantation. Insome embodiments the disorder associated with transplantation istransplant rejection, or graft versus host disease.

In some embodiments the disorder is associated with type I interferon,IL-10, IL-12, or IL-23 signaling. In some embodiments the disorder isassociated with type I interferon signaling. In some embodiments thedisorder is associated with IL-10 signaling. In some embodiments thedisorder is associated with IL-12 signaling. In some embodiments thedisorder is associated with IL-23 signaling.

Compounds of the invention are also useful in the treatment ofinflammatory or allergic conditions of the skin, for example psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, systemic lupus erythematosus, pemphigus vulgaris,pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosaacquisita, acne vulgaris, and other inflammatory or allergic conditionsof the skin.

Compounds of the invention may also be used for the treatment of otherdiseases or conditions, such as diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as ocular allergy, conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, diseasesaffecting the nose including allergic rhinitis, and inflammatory diseasein which autoimmune reactions are implicated or having an autoimmunecomponent or etiology, including autoimmune hematological disorders(e.g. hemolytic anemia, aplastic anemia, pure red cell anemia andidiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoidarthritis, polychondritis, scleroderma, Wegener granulamatosis,dermatomyositis, chronic active hepatitis, myasthenia gravis,Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory boweldisease (e.g. ulcerative colitis and Crohn's disease), irritable bowelsyndrome, celiac disease, periodontitis, hyaline membrane disease,kidney disease, glomerular disease, alcoholic liver disease, multiplesclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren'ssyndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis,interstitial lung fibrosis, psoriatic arthritis, systemic juvenileidiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis,vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minal change nephropathy), chronic granulomatousdisease, endometriosis, leptospiriosis renal disease, glaucoma, retinaldisease, ageing, headache, pain, complex regional pain syndrome, cardiachypertrophy, musclewasting, catabolic disorders, obesity, fetal growthretardation, hyperchlolesterolemia, heart disease, chronic heartfailure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma (allergic and non-allergic, mild,moderate, severe, bronchitic, and exercise-induced), acute lung injury,acute respiratory distress syndrome, eosinophilia, hypersensitivities,anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases,COPD (reduction of damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression), pulmonary disease,cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis.

In certain embodiments, the present invention provides a method oftreating alopecia areata.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic jubenileidiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome(CAPS), and osteoarthritis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is a T_(h)1 or T_(h)17mediated disease. In some embodiments the T_(h)17 mediated disease isselected from Systemic lupus erythematosus, Multiple sclerosis, andinflammatory bowel disease (including Crohn's disease or ulcerativecolitis).

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from Sjogren'ssyndrome, allergic disorders, osteoarthritis, conditions of the eye suchas ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernalconjunctivitis, and diseases affecting the nose such as allergicrhinitis.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of an autoimmune disorder, an inflammatory disorder, or aproliferative disorder, or a disorder commonly occurring in connectionwith transplantation.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

In one embodiment, the present invention provides a compositioncomprising a compound of formula I and one or more additionaltherapeutic agents. The therapeutic agent may be administered togetherwith a compound of formula I, or may be administered prior to orfollowing administration of a compound of formula I. Suitabletherapeutic agents are described in further detail below. In certainembodiments, a compound of formula I may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursbefore the therapeutic agent. In other embodiments, a compound offormula I may be administered up to 5 minutes, 10 minutes, 15 minutes,30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14hours, 15 hours, 16 hours, 17 hours, or 18 hours following thetherapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a compound of formula I and one or moreadditional therapeutic agents. Such additional therapeutic agents may besmall molecules or recombinant biologic agents and include, for example,acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®),antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), methotrexate (Rheumatrex®), gold salts such as goldthioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin(Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine(Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®),cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab(Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfmavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a compound of formula I and one or more additionaltherapeutic agents selected from non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, sulfasalazine(Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) andchloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such asgold thioglucose (Solganal®), gold thiomalate (Myochrysine®) andauranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®),azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil(Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and“anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®),golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab(Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®) and “anti-IL-6” agents such astocilizumab (Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from acetaminophen, non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®)and monoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatingsystemic lupus erythematosus comprising administering to a patient inneed thereof a compound of formula I and one or more additionaltherapeutic agents selected from acetaminophen, non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone,prednisolone, methylprednisolone, hydrocortisone, and the like,antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®),azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine®or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatingCrohn's disease, ulcerative colitis, or inflammatory bowel diseasecomprising administering to a patient in need thereof a compound offormula I and one or more additional therapeutic agents selected frommesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such asdiphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid bindingagents such as cholestyramine, alosetron (Lotronex®), lubiprostone(Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol(MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics orantispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies,steroids, and antibiotics such as Flagyl or ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a compoundof formula I and one or more additional therapeutic agents selected fromSingulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterolacetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterolxinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agentssuch as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®),inhaled corticosteroids such as prednisone, prednisolone, beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®),flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolynsodium (Intal®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgEantibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a compound offormula I and one or more additional therapeutic agents selected frombeta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA),levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate(Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate(Serevent®) and formoterol (Foradil®), anticholinergic agents such asipratropium bromide (Atrovent®) and tiotropium (Spiriva®),methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®,Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®,

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYKinhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and a Hedgehog (Hh)signaling pathway inhibitor. In some embodiments, the hematologicalmalignancy is DLBCL (Ramirez et al “Defining causative factorscontributing in the activation of hedgehog signaling in diffuse largeB-cell lymphoma” Leuk. Res. (2012), published online July 17, andincorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from bortezomib (Velcade®), and dexamethasone(Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a BTKinhibitor, wherein the disease is selected from inflammatory boweldisease, arthritis, systemic lupus erythematosus (SLE), vasculitis,idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis,psoriatic arthritis, osteoarthritis, Still's disease, juvenilearthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord'sthyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren'ssyndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis,Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison'sdisease, opsoclonus-myoclonus syndrome, ankylosing spondylosis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, autoimmune gastritis, pernicious anemia, celiac disease,Goodpasture's syndrome, idiopathic thrombocytopenic purpura, opticneuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome,Takayasu's arteritis, temporal arteritis, warm autoimmune hemolyticanemia, Wegener's granulomatosis, psoriasis, alopecia universalis,Behcet's disease, chronic fatigue, dysautonomia, membranousglomerulonephropathy, endometriosis, interstitial cystitis, pemphigusvulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, ahyperproliferative disease, rejection of transplanted organs or tissues,Acquired Immunodeficiency Syndrome (AIDS, also known as HIV), type 1diabetes, graft versus host disease, transplantation, transfusion,anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs,foods, insect poisons, animal hair, animal dander, dust mites, orcockroach calyx), type I hypersensitivity, allergic conjunctivitis,allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopicdermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, chronic graftrejection, colitis, conjunctivitis, Crohn's disease, cystitis,dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis,endometritis, enteritis, enterocolitis, epicondylitis, epididymitis,fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonleinpurpura, hepatitis, hidradenitis suppurativa, immunoglobulin Anephropathy, interstitial lung disease, laryngitis, mastitis,meningitis, myelitis myocarditis, myositis, nephritis, oophoritis,orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia,polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis,ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cellproliferative disorder, e.g., diffuse large B cell lymphoma, follicularlymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia,acute lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenicmarginal zone lymphoma, multiple myeloma (also known as plasma cellmyeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma,extranodal marginal zone B cell lymphoma, nodal marginal zone B celllymphoma, mantle cell lymphoma, mediastinal (thymic) large B celllymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis,breast cancer, prostate cancer, or cancer of the mast cells (e.g.,mastocytoma, mast cell leukemia, mast cell sarcoma, systemicmastocytosis), bone cancer, colorectal cancer, pancreatic cancer,diseases of the bone and joints including, without limitation,rheumatoid arthritis, seronegative spondyloarthropathies (includingankylosing spondylitis, psoriatic arthritis and Reiter's disease),Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis,bone cancer, bone metastasis, a thromboembolic disorder, (e.g.,myocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, deep venousthrombosis), inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis,psoriatic arthritis, juvenile arthritis, osteoarthritis, chronicidiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia,myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis,degenerative joint disease, vitiligo, autoimmune hypopituitarism,Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosisfungoides, acute inflammatory responses (such as acute respiratorydistress syndrome and ischemia/reperfusion injury), and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PBKinhibitor, wherein the disease is selected from a cancer, aneurodegenative disorder, an angiogenic disorder, a viral disease, anautoimmune disease, an inflammatory disorder, a hormone-related disease,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with ceil death,thrombin-induced platelet aggregation, chronic myelogenous leukemia(CIVIL), chronic lymphocytic leukemia (CLL), liver disease, pathologicimmune conditions involving T cell activation, a cardiovasculardisorder, and a CNS disorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PBKinhibitor, wherein the disease is selected from benign or malignanttumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cellcarcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, endometrium, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma or gastrointestinal cancer, especially colon carcinomaor colorectal adenoma or a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, (including, for example,non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termedHodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

In some embodiments the present invention provides a method of treatingor lessening the severity of a disease comprising administering to apatient in need thereof a compound of formula I and a Bel-2 inhibitor,wherein the disease is an inflammatory disorder, an autoimmune disorder,a proliferative disorder, an endocrine disorder, a neurologicaldisorder, or a disorder associated with transplantation. In someembodiments, the disorder is a proliferative disorder, lupus, or lupusnephritis. In some embodiments, the proliferative disorder is chroniclymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease,small-cell lung cancer, non-small-cell lung cancer, myelodysplasticsyndrome, lymphoma, a hematological neoplasm, or solid tumor.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of anautoimmune disorder, an inflammatory disorder, a proliferative disorder,an endocrine disorder, a neurological disorder, or a disorder associatedwith transplantation. The exact amount required will vary from subjectto subject, depending on the species, age, and general condition of thesubject, the severity of the infection, the particular agent, its modeof administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity in a biological sample comprising thestep of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting TYK2, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound. In certainembodiments, the invention relates to a method of irreversiblyinhibiting TYK2, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

In another embodiment, the invention provides a method of selectivelyinhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In someembodiments, a compound of the present invention is more than 2-foldselective over JAK1/2/3. In some embodiments, a compound of the presentinvention is more than 5-fold selective over JAK1/2/3. In someembodiments, a compound of the present invention is more than 10-foldselective over JAK1/2/3. In some embodiments, a compound of the presentinvention is more than 50-fold selective over JAK1/2/3. In someembodiments, a compound of the present invention is more than 100-foldselective over JAK1/2/3.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of TYK2 (or a mutant thereof) activity in a biological sampleis useful for a variety of purposes that are known to one of skill inthe art. Examples of such purposes include, but are not limited to,blood transfusion, organ-transplantation, biological specimen storage,and biological assays.

Another embodiment of the present invention relates to a method ofinhibiting protein kinase activity in a patient comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting activity of TYK2, or a mutant thereof, in a patientcomprising the step of administering to said patient a compound of thepresent invention, or a composition comprising said compound. Accordingto certain embodiments, the invention relates to a method of reversiblyor irreversibly inhibiting one or more of TYK2, or a mutant thereof,activity in a patient comprising the step of administering to saidpatient a compound of the present invention, or a composition comprisingsaid compound. In other embodiments, the present invention provides amethod for treating a disorder mediated by TYK2, or a mutant thereof, ina patient in need thereof, comprising the step of administering to saidpatient a compound according to the present invention orpharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other therapeutic compounds. In some embodiments, theother therapeutic compounds are antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin. The term “aromatase inhibitor” as used hereinrelates to a compound which inhibits estrogen production, for instance,the conversion of the substrates androstenedione and testosterone toestrone and estradiol, respectively. The term includes, but is notlimited to steroids, especially atamestane, exemestane and formestaneand, in particular, non-steroids, especially aminoglutethimide,roglethimide, pyridoglutethimide, trilostane, testolactone,ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestaneis marketed under the trade name Aromasin™. Formestane is marketed underthe trade name Lentaron™. Fadrozole is marketed under the trade nameAfema™. Anastrozole is marketed under the trade name Arimidex™.Letrozole is marketed under the trade names Femara™ or Femar™.Aminoglutethimide is marketed under the trade name Orimeten™. Acombination of the invention comprising a chemotherapeutic agent whichis an aromatase inhibitor is particularly useful for the treatment ofhormone receptor positive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed, under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the Axl receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAR,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC family, and/or membersof the cyclin-dependent kinase family (CDK) including staurosporinederivatives, such as midostaurin; examples of further compounds includeUCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196;isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) orAT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibitingthe activity of protein-tyrosine kinase inhibitors, such as compoundswhich target, decrease or inhibit the activity of protein-tyrosinekinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostinsuch as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “famesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase, and Bcl-2 inhibitors.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412. In some embodiments, the presentinvention provides a method of treating AML associated with an ITDand/or D835Y mutation, comprising administering a compound of thepresent invention together with a one or more FLT3 inhibitors. In someembodiments, the FLT3 inhibitors are selected from quizartinib (AC220),a staurosporine derivative (e.g. midostaurin or lestaurtinib),sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302,NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028,fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3inhibitors are selected from quizartinib, midostaurin, lestaurtinib,sorafenib, and sunitinib.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Heilman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SelCID™ CC-10004 (Celgene),VM554/UM565 (Vemalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2aagonists; A2b antagonists; and beta-2 adrenoceptor agonists such asalbuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol and pharmaceuticallyacceptable salts thereof. Suitable bronchodilatory drugs includeanticholinergic or antimuscarinic compounds, in particular ipratropiumbromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), andglycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Example 1. Synthesis of2-(2,6-difluorophenyl)-4-(indolin-6-ylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-1

Synthesis of compound 1.2 To a solution of compound 1.1 (300 mg 0.69mmol, 1.0 eq.) in 1-butanol (9.0 mL) were added tert-butyl6-aminoindoline-1-carboxylate (162 mg, 0.69 mmol, 1.0 eq.) and DIPEA(224 mg, 1.74 mmol, 2.5 eq.) at room temperature. Reaction mixture washeated at 85-90° C. for 2 hours. After completion of the reaction,mixture was poured into the water and extracted using ethyl acetate.Organic layer was washed with by brine solution, dried over sodiumsulfate and concentrated under reduced pressure. Crude was purified bycolumn chromatography to provide compound 1.1 (302 mg, 69.04%), MS (ES):m/z 630.6 [M+H]⁺.

Synthesis of compound I-1. A solution of compound 1.1 (302 mg, 0.48mmol, 1.0 eq.) in HBr/HOAc solution (33%, 6.0 mL) was stirred at roomtemperature for 45 minutes. After completion of the reaction, reactionmixture was poured into cold water, neutralized with NaHCO₃ andextracted with ethyl acetate (75 ml×2). Solvent was removed underreduced pressure and the crude was purified by column chromatography toafford pure compound I-1 (105 mg, 57.7%). MS (ES): m/z—380.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆): δ 8.88 (s, 1H), 8.85 (s, 1H), 7.61-7.57 (m, 1H),7.28-7.24 (t, 2H), 6.97-6.93 (m, 2H), 6.81-6.79 (dd, 1H), 5.62 (s, 1H),4.45 (s, 2H), 3.42-3.40 (t, 2H), 2.87-2.83 (t, 2H).

Example 2. Synthesis of2-(2,6-difluorophenyl)-4-((3,3-dimethylindolin-6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-2

Synthesis of compound 2.1. To a solution of compound 1.1 (130 mg 0.3mmol, 1.0 eq.) in 1-butanol (5.0 mL) was added tert-butyl6-amino-3,3-dimethylindoline-1-carboxylate (79 mg, 0.3 mmol, 1.0 eq.)and diisopropylethylamine (97 mg, 0.75 mmol, 2.5 eq.) at roomtemperature. Reaction was heated at 85-90° C. for 2 hours. Aftercompletion of the reaction, reaction mixture was poured into water andextracted using ethyl acetate. Organic layer was washed with by brinesolution, dried over sodium sulfate and concentrated under reducedpressure. Crude was purified by column chromatography to afford purecompound 2.1 (110 mg, 65.53%), MS (ES): m/z 558.6 [M+H]⁺.

Synthesis of compound I-2. A solution of compound 2.1 (110 mg, 0.19mmol, 1.0 eq.) in hydrogen bromide/CH₃COOH (33%, 4 ml) was stirred atroom temperature for 45 minutes. After completion of the reaction,mixture was poured into cold water, neutralized with NaHCO₃. Product wasextracted with ethyl acetate (75 mL×2). Solvent was removed underreduced pressure at 45° C. The crude was purified using columnchromatography and preparative TLC to afford pure compound I-2 (20 mg,24.9%). MS (ES): m/z—408.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 8.88 (s,1H), 8.85 (s, 1H), 7.62-7.57 (m, 1H), 7.28-7.24 (t, 2H), 6.94-6.92 (m,2H), 5.60 (s, 1H), 4.45 (s, 2H), 3.167-3.163 (d, 2H), 1.23 (s, 6H).

Example 3. Synthesis of compound2-(2,6-difluorophenyl)-4-((2,2-dimethylindolin-6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-3

Synthesis of compound 3.2. To a solution of compound 3.1 (1 g 4.60 mmol,1.0 eq.) in cyclohexane (8 mL) were added ter.-butyl2,2,2-trichloroacetimidate (2.05 ml, 11.51 mmol, 2.5 eq.), BF₃-Et₂O(0.11 ml) at room temperature under argon atmosphere for 15 minutes.Reaction mixture was stirred at room temperature for 16 hours. Aftercompletion of reaction, mixture was poured into water and extractedusing ethyl acetate. Organic layer was washed with by satd. NaHCO₃,dried over Na₂SO₄ and concentrated under reduced pressure. The crude waspurified using column chromatography to provide compound 3.2 (0.27 g,21.3%). MS (ES): No ionisation [M+H]⁺.

Synthesis of compound 3.3. Compound 3.2 (0.2 g, 0.73 mmol) was dissolvedin methyl chloroformate (2 mL). The reaction mixture was heated at 80°C. for 16 hrs. After completion of the reaction, water was added to themixture and extracted using dichloromethane. Organic layer was driedover sodium sulfate and concentrated under reduced pressure. The crudereaction mixture was purified by column chromatography to affordcompound 3.3 (0.12 g, 49.49%). MS (ES): m/z No ionisation [M+H]⁺.

Synthesis of compound 3.4. To a solution of compound 3.3 (0.050 g, 0.150mmol. 1.0 eq.) in xylene were added cesium carbonate (0.068 g, 0.211mmol), tricyclohexylphosphine tetrafluoroborate (0.004 g, 0.009 mmol,0.06 eq.), pivalic acid (0.005 g, 0.0452 mmol, 0.3 eq), and palladiumacetate (0.001 g, 0.0045 mmol, 0.03 eq). Reaction mixture was degassedusing argon atmosphere for 10 min. The reaction was stirred at 140° C.for 1 hour. After completion of the reaction, mixture was poured inwater, and product was extracted with ethyl acetate (50 mL×2). Solventwas removed under reduced pressure at 45° C. to get crude, which waspurified by column chromatography to afford pure compound 3.4 (0.035 g,92.63%). MS (ES): m/z 251 [M+H]⁺.

Synthesis of compound 3.5. To a suspension of Pd/C (10 mg) in methanol(10 ml) was added compound 3.4 (0.085 g, 0.339 mmol. 1.0 eq.) undernitrogen atmosphere. The mixture was purged with H₂ (gas) at roomtemperature for 2 hours. After completion of the reaction, the mixturewas filtered through celite. Solvent was removed under reduced pressureat 45° C. to afford compound 3.5 (0.070 g, 93.6%). MS (ES): m/z 221.3[M+H]⁺.

Synthesis of compound 3.6. To a solution of compound 3.5 (130 mg 0.301mmol, 1.0 eq.) in 1-butanol (2.0 mL) was added compound 3.5 (72 mg,0.331 mmol, 1.1 eq.) and DIPEA (0.15 mL, 0.903 mmol, 3 eq.) at roomtemperature. Reaction was heated at 90° C. for 3 hours. After completionof the reaction, mixture was poured into water and extracted using ethylacetate. Organic layer was washed with by brine solution. Organic layerwas dried over sodium sulfate and concentrated under reduced pressure.Crude was purified by column chromatography to afford pure compound 3.6(120 mg, 64.75%), MS (ES): m/z 616.7 [M+H]⁺.

Synthesis of compound I-3. A solution of compound 3.6 (0.120 g, 0.194mmol, 1.0 eq.) in HBr/HOAc (33%, 3 ml) was stirred at room temperaturefor 45 minutes. After completion of the reaction, the mixture was pouredinto cold water, neutralized with NaHCO₃ and product was extracted withethyl acetate (75 ml×2). Solvent was removed under reduced pressure at45° C. to get crude which was purified to afford pure compound I-3 (10mg, 12.59%). MS (ES): m/z—408.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ8.87 (d, 2H), 7.59 (m, 1H), 7.25 (dd, 2H), 6.91 (d, 2H), 6.75 (dd, 1H),5.64 (s, 1H), 4.45 (s, 2H), 2.67 (s, 2H), 1.20 (d, 6H).

Example 4. Synthesis of4-((5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-4

Synthesis of compound 4.2. To a solution of 4.1 (0.2 g, 0.9852 mmol, 1.0equiv) in DMSO (3 ml) were added TBAI (0.036 g, 0.0985 mmol, 0.1 equiv),(1R,5S)-8-oxa-3-zabicyclo[3.2.1]octane (0.162 g, 1.083 mmol, 1.1equiv.), and K₂CO₃ (0.544 g, 3.94 mmol, 4 equiv). Reaction mixture washeated at 120° C. for 2 hours. The reaction mixture was poured intowater and product was extracted with ethyl acetate. Organic layers werecombined and dried over sodium sulphate and concentrated under reducedpressure to obtain crude material which was purified using columnchromatography to furnish 4.2 (0.120 g, 51.77%). MS (ES): m/z 236[M+H]⁺.

Synthesis of compound 4.3. To a solution of compound 4.2 (0.120 g,0.5106 mmol, 1.0 equiv) in methanol (5 mL) was added with 10% Pd/C(0.012 mg) under nitrogen atmosphere. Suspension was purged with H₂ gasfor 3 hours. Reaction mixture was filtered through celite and obtainedfiltrate was concentrated under reduced pressure to get crude compound4.3 (0.105 g) which was used as such for the next step, MS (ES): m/z206.0 [M+H]⁺.

Synthesis of compound 4.5. To a solution of compound 4.4 (0.2 g, 0.4645mol, 1.0 equiv) in 1,4-dioxane (3 mL) were added compound 4.3 (0.104 g,0.5109 mmol, 1.1 equiv) and potassium carbonate (0.160 g, 1.161 mmol,2.5 equiv). The reaction mixture was degassed for 10 minutes using argongas, then Pd₂(dba)₃ (0.042 g, 0.0464 mmol, 0.1 equiv) and Xantphos(0.053 g, 0.0929 mmol, 0.2 equiv) were added. Suspension was degassedfor additional 5 minutes. The reaction was then heated at 110° C. for 2h. After completion of reaction, reaction mixture was poured in waterand product was extracted with ethyl acetate. Organic layers werecombined and dried over sodium sulphate and concentrated under reducedpressure to obtain crude material which was purified using columnchromatography to afford pure 4.5 (0.12 g, 43.1%). MS (ES): m/z 600.3[M+H]⁺.

Synthesis of compound I-4. The compound 4.5 was dissolved in HBr inacetic acid (2 ml) and stirred at room temperature for 1 h. Aftercompletion of the reaction, mixture was poured into water and basifiedwith saturated bicarbonate solution and product was extracted with ethylacetate. Organic layers were combined and dried over sodium sulphate andconcentrated under reduced pressure to obtain crude material which waspurified using column chromatography to get pure compound I-4 (0.052 g,57.8%). MS (ES): m/z 450.21 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHZ): 9.47 (s,1H), 8.80 (s, 1H), 8.34 (s, 1H), 7.94 (d, 1H), 7.60 (m, 1H), 7.40 (dd,1H), 7.25 (m, 2H), 7.10 (d, 1H), 4.40 (s, 4H), 3.36 (t, 2H), 2.80 (dd,2H), 1.83 (s, 4H).

Example 5. Synthesis of4-((4-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)phenyl)-amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-5

To a solution of 5.1 (0.1 g 0.26 mmol, 1.0 eq) in dry THF (5.0 mL) wasadded EDCl-HCl (0.1 g, 0.52 mmol, 2.0 eq) followed by HOBt (0.069 g,0.39 mmol, 1.5 eq) at 0° C. Solution was allowed to stir at 0° C. for 1hour. 8-oxa-3-azabicyclo[3.2.1]octane (0.035 g, 0.312 mmol, 1.2 eq) wasadded followed by DIPEA (0.1 g, 0.78 mmol, 3.0 eq). Reaction mixture wasallowed to warm to room temperature and was stirred overnight. Aftercompletion of the reaction, mixture was poured into water and extractedusing ethyl acetate (50 mL×2). Organic layer was washed with by brinesolution, dried over sodium sulfate and concentrated under reducedpressure. Crude was purified by column chromatography to afford purecompound I-5 (65 mg, 52.1%). MS (ES): M/z 478.53 [M+H]⁺, ¹H NMR (400MHz, DMSO-d₆): δ 9.226 (s, 1H), 8.963 (s, 1H), 7.828-7.849 (d, 2H),7.568-7.641 (m, 1H), 7.373-7.394 (d, 2H), 7.249-7.343 (m, 2H), 4.505(2H), 4.358 (m, 2H), 7.193 (m, 1H), 3.727-3.763 (m, 1H), 2.950-2.976 (m,2H), 1.771 (m, 6H).

Example 6. Synthesis of2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo-[3,4-d]pyrimidin-4-yl)amino)phenyl)-2-hydroxypropanoicacid, I-6

Synthesis of compound 6.2. To a suspension of NaH (0.740 g, 18.45 mmol,1.5 eq) in DMF (10 mL) at 0° C. was added 6.1 (0.76 g, 6.15 mmol, 0.5eq) followed by ethyl 2-chloropropionate (1.68 g, 12.3 mmol, 1 eq)dropwise via a syringe. The reaction was stirred at 0° C. for 1 hourthen for 2 hours at room temperature. Benzaldehyde (0.98 g, 9.22 mmol,0.75 eq) was added and reaction was purged with oxygen for 16 hours. Thereaction mixture was quenched with ice; then dil. HCl was added. Productwas extracted with ethyl acetate (20 mL×2). Organic layers were combinedand dried over sodium sulphate and concentrated under reduced pressure.Crude was purified using column chromatography to furnish 6.2 (0.466 g,31.6%). MS (ES): m/z no ionisation [M+H]⁺.

Synthesis of compound 6.3. To a solution of 6.2 (0.266 g, 1.112 mmol,1.0 eq) in methanol (3 mL) and water (3 mL) was added NH₄Cl (0.350 g,5.564 mmol, 5.0 eq) followed by iron powder (0.311 g, 5.564 mmol, 5.0eq) for 1 h. Reaction mixture was heated at 80° C. for 2 hours. Reactionmixture was filtered through celite, washed with methanol and obtainedfiltrate was concentrated under reduced pressure to get crude 6.3 (0.2g, 85.96%) which was used as such for the next step, MS (ES): m/z 210[M+H]⁺.

Synthesis of compound 6.4. To a solution of 1.1 (0.3 g, 0.69 mmol, 1.0eq) in 1-butanol (5 mL) were added 6.3 (0.159 g, 0.764 mmol, 1.1 eq) andDIPEA (0.4 mL, 2.08 mmol, 3 eq). Reaction was stirred at 100° C. for 2hours. After completion of the reaction, reaction mixture was pouredinto water and product was extracted with EtOAc (100 mL×2). Organiclayer were combined, dried over sodium sulphate and concentrated underreduced pressure. Crude was purified purified by column chromatographyto furnish 6.4 (0.3 g, 71.4%). MS (ES): m/z 605.3 [M+H]⁺.

Synthesis of compound 6.5. Compound 6.4 (0.3 g, 0.496 mmol, 1.0 eq) wasdissolved in HBr/HOAc mixture (3 mL) and stirred at room temperature for1 hour. After completion, reaction mixture was poured into water andbasified with saturated bicarbonate solution. Product was extracted withEtOAc (100 mL×2). Organic layers were combined, dried over sodiumsulphate and concentrated under reduced pressure. The crude was purifiedusing column chromatography to provide 6.5 (0.125 g, 55.44%). MS (ES):m/z 455.2 [M+H]⁺.

Synthesis of compound I-6. To a solution of 6.5 (0.125 g, 0.275 mmol,1.0 eq) in MeOH (3 mL) and water (3 mL) was added NaOH (0.066 g, 1.65mmol, 6.0 eq). Reaction was stirred at room temperature for 1 hour.Solvent was concentrated under reduced pressure and reaction mixture wasacidified with diluted HCl and extracted with EtOAc (25 mL×2). Organiclayers were combined, dried over sodium sulphate and concentrated underreduced pressure. The crude was triturated with diethyl ether andpentane to get pure compound I-6 (0.08 g, 68.2%). MS (ES): m/z 427.3[M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz): 12.67 (s, 1H), 9.081 (s, 1H), 8.90(s, 1H), 7.70 (d, 2H), 7.60 (m, 1H), 7.47 (d, 2H), 7.27 (t, 2H), 5.76(s, 1H), 4.48 (s, 2H), 1.6 (s, 3H).

Example 7. Synthesis of(S)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-2-hydroxypropanoicacid, I-7

Compound I-7 was obtained by chiral separation of compound I-6. MS (ES):m/z [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ 12.65 (s, 1H), 9.079 (s, 1H),8.904 (s, 1H), 7.70-7.72 (d, 2H), 7.60 (m, 1H), 7.58 (d, 2H), 7.25-7.30(m, 2H), 4.48 (s, 2H), 1.60 (s, 3H).

Example 8. Synthesis of(R)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-2-hydroxypropanoicacid, I-8

Compound I-8 was obtained by chiral separation of compound I-6. MS (ES):m/z [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ 9.06 (s, 1H), 8.88 (s, 1H),7.68-7.70 (d, 2H), 7.58-7.62 (m, 1H), 7.47-7.49 (d, 2H), 7.25-7.29 (m,2H), 4.47 (s, 2H), 1.58-1.62 (d, 3H).

Example 9. Synthesis of compound2-amino-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-N-ethylpropanamide,I-9

Synthesis of compound 9.2. To a solution of 9.1 (1 g 7.1 mmol, 1.0 eq.)in CH₂Cl₂ (10 mL) was added diphenylmethanimine (1.3 g, 7.1 mmol, 1.0eq.). Reaction was stirred at ambient temperature for 16 hours. Aftercompletion of the reaction, mixture was poured into water (200 mL) andextracted using EtOAc (100 mL×3). Organic layer was washed withsaturated brine solution, dried over sodium sulfate and concentratedunder reduced pressure. Crude was purified using column chromatographyto afford 9.2 (1.4 g, 54%). MS (ES): m/z 268.33 [M+H]⁺.

Synthesis of compound 9.3. To a stirred solution of 9.2 (1.4 g, 0.52mmol, 1.0 eq) and 1-bromo-3-nitrobenzene (2.1 g, 10.5 mmol, 2.0 eq) inTHF (18 mL) and DMF (4 mL) at −78° C. was added a solution Potassiumtert-butoxide (0.88 g 10.5 mmol, 2.0 eq.) in THF (5 mL) dropwise.Reaction mixture was stirred for further 30 minutes, then treated with2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.4 g, 6.3 mmol, 1.20 eq) inTHF (2 mL). After 5 minutes of stirring the cooling bath was removed andthe reaction mixture allowed to reach ambient temperature. Compound wasdirectly purified by column chromatography to afford pure 9.3 (1.2 g,49.03%), MS (ES): m/z 468.3 [M+H]⁺.

Synthesis of compound 9.4. To a solution of 9.3 (1.2 g) in acetonitrilewas added 6 N HCl solution (20 mL). Reaction was stirred at roomtemperature for 6 hours. Upon completion, reaction mixture was pouredinto satd. Na₂CO₃ (500 mL) and extracted with EtOAc (200 mL×3). Organiclayers were combined, dried over sodium sulphate and concentrated underreduced pressure to obtain crude which was purified by columnchromatography, to get pure 9.4 (0.7 g, 90%). MS (ES): m/z 304.11[M+H]⁺.

Synthesis of compound 9.5. To a solution of 9.4 (500 mg 1.65 mmol, 1.0eq.) in EtOAc:H₂O (10 mL) were added Boc anhydride (680 mg, 3.1 mmol,1.9 eq.) and lithium carbonate (260 mg, 3.6 mmol, 2.2 eq.). Reaction washeated at 60° C. for 24 hours. Upon completion, reaction mixture waspoured into water (100 mL) and extracted with EtOAc (50 mL×3). Organiclayers were combined, dried over sodium sulphate and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to furnish 9.5 (0.55 g, 59.1%). MS (ES): m/z 404.11[M+H]⁺.

Synthesis of compound 9.6. A solution of 9.5 (500 mg 1.24 mmol, 1.0 eq.)in MeOH/H₂O water (10 mL) was charged with added LiOH (0.16 g, 3.7 mmol,3 eq.) and stirred at ambient temperature for 3 hours. Upon completion,reaction mixture was poured into water (100 mL) and extracted with ethylacetate (50 mL×3). Organic layers were combined, dried over sodiumsulphate and concentrated under reduced pressure to get 9.6 (0.5 g,94%). MS (ES): m/z 390.2 [M+H]⁺.

Synthesis of compound 9.7. To a solution of 106.6 (500 mg 1.28 mmol, 1.0eq.) in THF (2.0 mL) was added Ethylamine (1M solution in THF) (0.7 mL,1.59 mmol, 1.2 eq.), HATU (720 mg 1.92 mmol, 1.5 eq.) and DIPEA (0.7 ml,3.8 mmol, 3 eq.) at 0° C. The reaction was stirred at room temperaturefor 16 hours. Upon completion, reaction mixture was poured into water(100 mL) and extracted using EtOAc (50 mL×3). Organic layers werecombined, washed with saturated brine solution, dried over sodiumsulfate and concentrated under reduced pressure. Resulting crude waspurified by column chromatography to afford 9.7 (0.3 g, 56%). MS (ES):m/z 417.27 [M+H]⁺.

Synthesis of compound 9.8. To a suspension of Pd/C (100 mg) in MeOH (15ml) was added 9.7 (0.3 g, 0.75 mmol. 1.0 eq.) under nitrogen atmosphere.Reaction mixture was purged with H₂ gas at room temperature for 12hours. After completion of the reaction, reaction mixture was filterthrough celite. Solvent was removed under reduced pressure to afford 9.8(0.12 g, 54%). MS (ES): m/z 308.7 [M+H]⁺

Synthesis of compound 9.9. To a solution of 1.1 (91 mg 0.21 mmol, 1.0eq.) in 1-butanol (2.0 mL) was added 1.7 (65 mg, 0.21 mmol, 1.0 eq.) andDIPEA (0.11 mL, 0.63 mmol, 3 eq.) at room temperature. Reaction wasstirred at 90° C. for 3 hours. Upon completion mixture was poured intowater (50 mL) and extracted using EtOAc (30 mL×3). Organic layers werecombined, washed with saturated brine solution, dried over sodiumsulfate and concentrated under reduced pressure. The crude was purifiedusing column chromatography to afford 9.9 (0.08 g, 54%). MS (ES): m/z703.2 [M+H]⁺

Synthesis of compound I-9. A solution of 9.9 (0.08 g, 0.13 mmol, 1.0eq.) in HBr/HOAc solution (33%, 3 mL) was stirred at room temperaturefor 45 minutes. After completion of the reaction, mixture was pouredinto cold water, neutralized with NaHCO₃ and extracted with EtOAc (75mL×2). Solvent was removed under reduced pressure, and crude purified bycolumn chromatography to afford I-9 (35 mg, 68%). MS (ES): m/z—408.3[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ 9.04 (s, 1H), 8.89 (s, 1H), 7.90(t, 1H), 7.68 (d, 2H), 7.60 (t, 1H), 7.43 (d, 2H), 7.27 (t, 2H), 4.47(s, 2H), 3.07-3.02 (m, 2H), 1.51 (d, 3H), 0.98 (t, 3H).

Example 10. Synthesis of2-(2,6-difluorophenyl)-4-((3,3-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-10

Synthesis of compound 10.2. To a solution of 10.1 (7.0 g, 54.54 mmol,1.0 equiv) and pivaloyl chloride (6.7 mL, 57.0 mmol, 1.05 equiv) intoluene was added Et₃N (7.7 mL, 57.0 mmol, 2.5 equiv) and stirred at 60°C. for 16 hours. Upon completion, reaction mixture was poured into water(500 mL) and extracted with EtOAc (200 mL×3). Organic layers werecombined, dried over sodium sulphate and concentrated under reducedpressure to obtain crude which was purified by column chromatography toprovide pure 10.2 (9.0 g, 77.7%). MS (ES): m/z 213.3 [M+H]⁺.

Synthesis of compound 10.3. To a solution of 10.2 (9 g, 42 mmol, 1 eq)in THF (90 mL) was added tert-Butyllithium (1.6 M in pentane) (62 mL,90.0 mmol, 2.2 eq) at −78° C. Reaction mixture was stirred at −78° C.for 3 hours. A solution of iodine (12.7 g, 50.0 mmol, 1.2 eq) in THF (40mL) was added dropwise, at −78° C. Reaction was warmed to ambienttemperature and stirred for 2 hours. Upon completion, reaction mixturewas poured in diluted HCl (200 mL) and extracted with ethyl acetate (200mL×3). Organic layers were combined, dried over sodium sulphate andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to get 10.3 (8.0 g, 55.84%), MS (ES): m/z 339.3[M+H]⁺.

Synthesis of compound 10.4. To a solution of 10.3 (8.0 g, 23.63 mmol,1.0 eq) in 1-4 dioxane was added 2N HCl solution (20 mL). Reaction wasstirred at 80° C. for 3 hours. Reaction mixture was poured in saturatedsolution of NaHCO₃ (500 mL) and extracted with EtOAc (200 mL×3). Organiclayers were combined, dried over sodium sulphate and concentrated underreduced pressure to obtain crude which was purified by columnchromatography, to provide 10.4 (4.2 g, 70%). MS (ES): m/z 255.46[M+H]⁺.

Synthesis of compound 10.5. To a solution of 10.4 (1.5 g, 5.9 mmol, 1.0eq) in THF was added 3-bromo-2-methylprop-1-ene (0.95 g, 7.08 mmol, 1.2eq) and potassium tert-butoxide (0.8 g, 7.08 mmol, 1.2 eq). Reaction wasand stirred at room temperature for 3 hours. Reaction mixture was pouredin water (200 mL) and extracted with EtOAc (100 mL×3). Organic layerswere combined and dried over sodium sulphate, concentrated under reducedpressure to obtain crude which was purified by column chromatography toprovide 110.5 (1.5 g, 82%). MS (ES): m/z 309.55 [M+H]⁺.

Synthesis of compound 10.6. To a solution of 10.5 (1.5 g, 4.48 mmol, 1.0eq) in toluene (15 mL) was added potassium formate (500 mg, 5.8 mmol,1.2 eq), tetra-butyl ammonium chloride (1.6 g, 5.8 mmol, 1.2 eq) andEt₃N (2 mL, 1.4 mmol, 3 eq) at room temperature under argon bubbling for15 minutes. To the above reaction mixture was added Pd(OAc)₂ (53 mg,0.29 mmol, 0.1 eq) under argon bubbling for 10 minutes. Reaction mixturewas heated at 100° C. for 1 hour. After completion of the reaction,reaction mixture was poured into water (100 mL) and extracted usingethyl acetate (50 mL×3). Organic layers were washed with by brinesolution, combined and dried over sodium sulphate and concentrated underreduced pressure. Resulting crude was purified by column chromatographyto provide 10.6 (0.8 g, 90%). MS (ES): m/z 183.5 [M+H]⁺.

Synthesis of compound 10.7. To a solution of 10.6 (0.6 g, 3.2 mmol, 1.0eq) and Boc-anhydride (1.0 g, 4.86 mmol, 1.5 eq) in dichloromethane wasadded DMAP (39 mg, 0.32 mmol, 0.1 eq). Reaction was stirred at roomtemperature for 1 hour. Upon completion, mixture was poured into water(100 mL) and extracted with EtOAc (50 mL×3). Organic layers werecombined, dried over sodium sulphate and concentrated under reducedpressure to obtain crude material. The crude was purified by columnchromatography to provide 10.7 (0.8 g, 86%). MS (ES): m/z 283.2 [M+H]⁺.

Synthesis of compound 10.8. To a solution of 10.7 (0.2 g 0.70 mmol, 1.0eq) in dry THF (5.0 mL) was added LHMDS (1.0 M in THF) (2.1 mL, 2.1mmol, 3.0 eq) at room temperature under argon bubbling for 15 minutes.To the above reaction mixture was added Pd₂(dba)₃ (62 mg, 0.068 mmol,0.1 eq) and 2-Biphenyl)di-tert-butylphosphine, (48 mg, 0.021 mmol, 0.2eq) under argon bubbling for 10 minutes. Reaction mixture was heated at60° C. temperature for 2 hours. After completion of the reaction,reaction mixture was poured into water (50 mL) and extracted using ethylacetate (30 mL×3). Organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude material. Crude was purified by column chromatography to provide10.8 (0.08 g, 43.0%). MS (ES): m/z 264.2 [M+H]⁺.

Synthesis of compound 10.9. To a solution of 4.4 (0.10 g 0.23 mmol, 1.0eq) in dry dioxane (5.0 mL) was added 10.8 (67 mg, 0.23 mmol, 1.0 eq),K₂CO₃ (0.095 g, 0.60 mmol, 3.0 eq.) at room temperature under argonbubbling for 15 minutes. To the above reaction mixture was addedPd₂(dba)₃ (21 mg, 0.023 mmol, 0.1 eq) and Xantphos (26 mg, 0.046 mmol,0.2 eq) under argon bubbling for 10 minutes. Reaction mixture was heatedat 105° C. temperature for 3-4 hours. After completion of the reaction,reaction mixture was poured into water and extracted using ethylacetate. Organic layers were combined, washed with brine, then driedover sodium sulphate and concentrated under reduced pressure to obtaincrude material. Crude was purified by column chromatography to furnish10.9 (0.08 g, 53.0%). MS (ES): m/z 658.20 [M+H]⁺.

Synthesis of compound I-10. A solution of 10.9 (80 mg) in HBr/HOAcsolution (33%, 5 ml) was stirred at room temperature for 1 hour. Aftercompletion of the reaction, reaction mixture was poured into cold water,neutralized with NaHCO₃ and extracted with ethyl acetate (50 ml×2).Solvent was removed under reduced pressure and resulting crude waspurified by column chromatography to furnish compound I-10 (30 mg,60.0%). MS (ES): m/z 501.58 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ 9.48(s, 1H), 8.82 (s, 1H), 8.38 (s, 1H), 7.60-7.52 (m, 1H), 7.27-7.23 (m,3H), 6.54 (s, 1H), 6.15 (d, 1H), 4.41 (s, 2H), 3.20 (s, 2H), 1.21 (s,6H).

Example 12. Synthesis of2-(2,6-difluorophenyl)-4-((4-((1,3-dihydroxypropan-2-yl)oxy)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-12

Synthesis of compound 12.1. To a solution of 1.1 (0.140 g, 0.324 mmol,1.0 eq.) in DMSO (2 mL), 4-(oxetan-3-yloxy)aniline (0.051 g, 0.308 mmol,0.95 eq) and DIPEA (0.16 mL, 0.974 mmol, 3.0 eq) were added at roomtemperature. Reaction mixture was heated at 90° C. for 1 hour. Aftercompletion of the reaction, mixture was poured into cold water andextracted using ethyl acetate (20 mL×2). Organic layers were combinedand dried over sodium sulfate and concentrated under reduced pressure.Crude was purified by column chromatography to afford 12.1 (0.130 g,71.53%). MS (ES): m/z 560.5 [M+H]⁺

Synthesis of compound I-12. A solution of 12.1 (0.130 g, 0.232 mmol, 1eq) in TFA (6 mL) was heated at 70° C. for 8 hours. After completion ofthe reaction, reaction mixture was poured in cold water, neutralizedwith saturated sodium bicarbonate solution and extracted with ethylacetate (10 mL×2). Solvent was removed under reduced pressure andresulting crude was purified using column chromatography to provide I-12(0.030 g, 30.2%). MS (ES): m/z 428.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆):δ 8.96 (s, 1H), 8.84 (s, 1H), 7.61-7.51 (m, 3H), 7.27-7.23 (t, 2H),6.97-6.94 (d, 2H), 4.78-4.75 (t, 2H), 4.46 (s, 2H), 4.21-4.18 (q, 1H),3.60-3.50 (m, 4H).

Example 13. Synthesis of compound2-(2,6-difluorophenyl)-4-((4-methoxybenzyl)-amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-oneI-13

Synthesis of compound 13.1. To a solution of 1.1 (0.150 g 0.348 mmol,1.0 eq) in 1-butanol (2.0 mL) was added 4-Methoxy benzyl amine (0.047 g,0.348 mmol, 1.0 eq) and DIPEA (0.18 ml, 1.04 mmol, 3 eq) at roomtemperature. Reaction mixture was stirred at 120° C. for 3 hours. Aftercompletion of the reaction, mixture was poured into water and extractedusing ethyl acetate. Organic layer was washed with brine, dried oversodium sulfate and concentrated under reduced pressure. Crude waspurified by column chromatography to afford pure 13.1 (0.110 g, 59.5%),MS (ES): m/z 533.6 [M+H]⁺

Synthesis of compound I-13. To a solution of 13.1 (0.11 g, 0.206 mmol,1.0 eq.) in HBr/HOAc solution (33%, 3 ml) was stirred at roomtemperature for 1 hour. After completion of reaction, mixture was pouredin cold water, neutralized with NaHCO₃ and extracted with ethyl acetate(25 mL×2). Solvent was removed under reduced pressure and resultingcrude purified using column chromatography to provide I-13 (0.045 g,56.9%). MS (ES): m/z—383.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 8.59 (s,1H), 7.87 (m, 1H), 7.56 (m, 1H), 7.29-7.21 (m, 4H), 6.86 (d, 2H), 4.60(d, 2H), 4.36 (s, 2H), 3.71 (s, 3H).

Example 14. Synthesis of2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-N-ethyl-2-hydroxypropanamide,I-14

Synthesis of compound 14.2. To a solution of 14.1 (5.0 g, 30.3 mmol, 1.0eq) in CH₂Cl₂ (50 mL) was added TMSCN (4.55 mL, 36.34 mmol, 1.2 eq)followed by TiCl₄ (1.14 g, 6.05 mmol, 0.2 eq) drop wise at roomtemperature. The reaction was stirred at room temperature for 18 hours.The reaction mixture was quenched with ice cold water and product wasextracted with CH₂Cl₂ (50 mL×2). Organic layers were combined, driedover sodium sulphate and concentrated under reduced pressure to obtain14.2 (5.8 g, 99.69%). MS (ES): m/z No ionisation [M+H]⁺.

Synthesis of compound 14.3. To a solution of 14.2 (5.8 g, 30.2 mmol, 1.0eq) in 1,4-dioxane (100 mL) was added cone. HCl (50 mL, eq). Reactionmixture was heated at 120° C. for 5 hours. Reaction mixture wasconcentrated under reduced pressure. Residue was dissolved in ethylacetate, washed with saturated sodium bicarbonate solution. Organiclayer was separated, dried over sodium sulaphate and concentrated underreduced pressure to obtain 14.3 (4.7 g, 73.74%) which was used as suchfor the next step, MS (ES): m/z 210 [M+H]⁺

Synthesis of compound 14.4. To a solution of 14.3 (4.7 g, 22.3 mmol, 1.0eq) in DMF (50 mL) was added ethyl amine (13.4 mL, 26.7 mmol, 1.2 eq),DIPEA (7.62 mL, 44.5 mmol, 2 eq) and HATU (10.16 g, 26.7 mmol, 1.2 eq).The reaction mixture was stirred at room temperature for 1 hour. Uponcompletion mixture was diluted with EtOAc (100 mL) and washed withsaturated NaHCO₃. Organic layer was dried over sodium sulphate andconcentrated under reduced pressure to obtain 14.4 (3.6 g, 67.9%). MS(ES): m/z 239.3 [M+H]⁺.

Synthesis of compound 14.5. Compound 14.4 (3.6 g, 15.1 mmol, 1.0 eq) wasdissolved in MeOH (3 mL) and added to 10% Pd/C. Hydrogen gas was bubbledthough reaction mixture for 2 hours. After completion of the reaction,reaction mixture was filtered through celite. Filtrate was concentratedunder reduced pressure to obtain 14.5 (3.12 g, 99.14%). MS (ES): m/z209.2 [M+H]⁺.

Synthesis of compound 14.6. To a solution of 1.1 (0.3 g, 0.69 mmol, 1.0eq) in 1-butanol (5 mL) was added 14.5 (0.16 g, 0.76 mmol, 1.1 eq) andDIPEA (0.4 mL, 2.08 mmol, 3.0 eq). The reaction was stirred at 120° C.for 2 hours. After completion of the reaction, mixture was poured intowater and product was extracted with EtOAc (50 mL×2). Organic layerswere combined and dried over sodium sulphate and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to furnish 14.6 (0.35 g, 83.46%). MS (ES): m/z 604.5[M+H]⁺.

Synthesis of compound I-14. Mixture of 14.6 (0.3 g, 0.49 mmol, 1.0 eq)and HBr/HOAc (5 mL) was stirred at room temperature for 1 hour. Reactionmixture was neutralized using saturated NaHCO₃ and extracted with EtOAc(25 mL×2). Organic layers were combined, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to furnish I-14 (0.17 g, 75.4%). MS (ES): m/z454.7 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.05 (s, 1H), 8.89 (s, 1H),7.83-7.86 (t, 1H), 7.66-7.68 (d, 2H), 7.58-7.60 (m, 1H), 7.46-7.48 (d,2H), 7.25-7.29 (m, 2H), 6.01 (s, 1H), 4.47 (s, 2H), 3.03-3.08 (m, 2H),1.58 (s, 3H), 0.94-0.98 (t, 3H).

Example 15. Synthesis of(S)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-N-ethyl-2-hydroxypropanamide,I-15

Compound I-15 was obtained by chiral separation of compound I-14. MS(ES): m/z 454.7 [M+H]⁺, ¹H NMR (400 MHz, DMSO): δ 9.05 (s, 1H), 8.89 (s,1H), 7.84-7.87 (t, 1H), 7.66-7.68 (d, 2H), 7.58-7.62 (m, 1H), 7.46-7.48(d, 2H), 7.24-7.29 (t, 2H), 6.01 (s, 1H), 4.47 (s, 2H), 2.99-3.08 (m,2H), 1.58 (s, 3H), 0.94-0.98 (t, 3H)

Example 16. Synthesis of(R)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-N-ethyl-2-hydroxypropanamide.I-16

Compound I-16 was obtained by chiral separation of compound I-14. MS(ES): m/z 454.54 [M+H]⁺, ¹H NMR (400 MHz, DMSO): δ 9.05 (s, 1H), 8.89(s, 1H), 7.84-7.87 (t, 1H), 7.66-7.68 (d, 2H), 7.58-7.62 (m, 1H),7.46-7.48 (d, 2H), 7.25-7.29 (t, 2H), 6.01 (s, 1H), 4.47 (s, 2H),3.01-3.07 (m, 2H), 1.58 (s, 3H), 0.94-0.98 (t, 3H).

Example 17. Synthesis of2-(2,6-difluorophenyl)-4-((2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-17

Synthesis of compound 17.2 To a solution of 17.1 (5.0 g, 39.0 mmol, 1.00eq) in ethoxyethene (11.25 g, 156.0 mmol, 4.0 eq) was added palladiumacetate slowly. Reaction was stirred at room temperature for 20 h. Aftercompletion of the reaction, the resulting solution was filtered throughcelite, washed with ethyl acetate and filtrate was distilled underreduced pressure to afford crude material which was purified by columnchromatography to afford pure 17.2 (1.0 g, 12.92%). MS (ES): m/z 199.1[M+H]⁺.

Synthesis of compound 17.4. To a solution of 17.3 (5.0 g, 54.6 mmol) inacetic acid (10 ml) was added sodium acetate (8.938 g, 109.0 mmol, 2.0eq) and iodine monochloride (4.069 g, 65.5 mmol, 1.2 eq). Reactionmixture was heated at 70° C. for 20 hours. After completion of thereaction, mixture was concentrated under reduced pressure and residuewas diluted with water and basified with sodium bicarbonate solution.Compound was extracted in EtOAc and washed with brine. Organic layer wasseparated, dried over sodium sulphate and concentrated under reducedpressure to afford crude material which was purified by chromatographyusing 12% to afford pure 17.4 (2.8 g, 28.2%), m/z=255.1 [M+H]⁺.

Synthesis of compound 17.5. In a seal tube 17.4 (0.200 g, 0.78 mmol, 1eq) and 17.2 (0.202 g, 1.02 mmol, 1.3 eq) was dissolved in DMF (5 mL).LiOH (0.095 g, 2.34 mmol, 3.0 eq) was added into the reaction mixture.Reaction mixture was degassed by argon gas for 10-15 mins. PdCl₂(dppf)(0.063 g, 0.078 mmole, 0.1 eq.) was then added. Reaction mixture wasfurther degassed by argon gas for 10 min. Reaction mixture was heatedwith stirring at 70° C. for 16 hours, After completion of the reaction,water was added and product was extracted with EtOAc (2×50 ml), organiclayer was separated, dried over sodium sulphate and concentrated underreduced pressure to afford crude material which was purified by columnchromatography to afford pure compound 17.5 (0.04 g, 25.62%). MS (ES):m/z 199.2 [M+H]⁺.

Synthesis of compound 17.6. A solution of 17.5 (0.04 g, 0.202 mmol, 1.00eq) in MeOH (1 mL) and HCl (0.1 ml) was heated to reflux for overnight.After completion of the reaction, mixture was concentrated and residuewas basifed with K₂CO₃ and extracted with EtOAc (2×50 ml). Organic layerwas dried over sodium sulphate and concentrated under reduced pressureto afford crude material which was purified by column chromatography toafford pure compound 17.6 (0.025 g, 81.4%). MS (ES): m/z 153.5 [M+H]⁺.

Synthesis of compound 17.7. A solution of 17.6 (0.25 g, 1.10 mmol, 1.00eq) and a Borane dimethyl sulfide complex solution (2.0M in THF) (2 mL)in THF (1.0 mL) was heated at 68° C. for 3 h. Reaction mixture wascooled to room temperature and poured in water; product was extractedwith EtOAc (50 mL×3). Combined organic layers were washed with brine,dried over sodium sulphate and concentrated under reduced pressure. Theresidue was purified using silica gel column to afford the compound 17.7(0.08 g, 31.58, MS (ES): m/z 155.6 [M+H]⁺.

Synthesis of compound 17.8. A solution of 17.7 (0.08 g, 0.519 mmol, 1.00eq), Di-tert-butyl-dicarbonate (0.191 g, 0.876 mmol, 1.5 eq) and DMAP(0.01 g, 0.058 mmol, 0.1 eq) in THF (10 mL) was stirred at roomtemperature for 3 hours. After completion, the reaction was diluted withwater and product was extracted with ethyl acetate (25 mL×3) and washedwith brine. The combined organic layers were dried and concentratedunder vacuum. Crude was purified by column chromatography to afford 17.8(0.06 g, 45.52%). MS (ES): m/z 255.1 [M+H]⁺.

Synthesis of compound 17.9. A solution of 17.8 (0.04 g 0.157 mmol, 1.0eq) in dry THF (0.4 mL) was degassed at room temperature under argon for15 minutes. To the above reaction mixture was added Pd₂(dba)₃ (0.014 g,0.0157 mmol, 0.1 eq) and 2-Biphenyl-di-tert-butylphosphine (0.01 g,0.031 mmol, 0.2 eq) under argon purge for 10 minutes followed by LHMDS(7.8 mg, 0.047 mmol, 3.0 eq). Reaction mixture was heated at 68° C. for1 hour. After completion of the reaction, reaction mixture was pouredinto water and extracted using EtOAc (25 mL×2). Organic layer was washedwith brine. Organic layer was dried over sodium sulfate and concentratedunder reduced pressure. Crude was purified using column chromatographyto afford pure 17.9 (0.028 g, 75.78%). MS (ES): m/z 254.1 [M+H]⁺.

Synthesis of compound 17.91. To a solution of 4.4 (0.08 g, 0.18 mmol,1.0 eq) and 17.9 (0.043 g, 0.186 mmol, 1.0 eq) in 1,4-dioxane (2 mL) wasadded K₂CO₃ (0.051 g, 0.580 mmol, 3.0 eq). Reaction mixture was degassedunder argon gas for 5-10 min. and Pd₂(dba)₃ (0.016 g, 0.018 mmol, 0.1eq) followed by Xantphos (0.01 g, 0.018 mmol, 0.2 eq) was added andagain degassed under argon for 5 min. Reaction mixture was heated at 90°C. for 4 hours. After completion of the reaction, mixture was pouredinto water and product was extracted with EtOAc. Organic layers werecombined and dried over sodium sulphate and concentrated under reducedpressure to obtain crude material. Crude was purified by columnchromatography to get pure 133.91 (0.035 g, 29.94%). MS (ES): m/z 630.1[M+H]⁺.

Synthesis of compound I-17. A solution of 17.91 (0.035 g, 0.081 mmol.1.0 eq.) in HBr/HOAc (33%, 1 ml) was stirred at room temperature for 1hour. After completion of the reaction, mixture was poured into coldwater, neutralized with Na₂CO₃ solution and product was extracted withethyl acetate (25 mL×3). Solvent was removed under reduced pressure toget crude material which was purified by column chromatography to affordpure I-17 (0.012 g, 56.91%). MS (ES): m/z 468.1 [M+H]⁺, ¹H NMR (400 MHz,DMSO-d⁶): δ 9.39 (s, 1H), 8.81 (s, 1H), 8.48 (s, 1H), 7.71 (s, 1H),7.60-7.55 (m, 1H), 7.27-7.23 (t, 2H), 6.55 (s, 1H), 6.02 (s, 1H), 4.39(s, 2H), 3.78-3.67 (t, 2H), 2.92-2.88 (t, 2H).

Example 18. Synthesis of2-(2,6-difluorophenyl)-4-((2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-7-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-18

Synthesis of compound 18.2. Compound 18.1 (2.0 g, 9.1 mmol, 1.0 eq),3-bromopropan-1-ol (1.9 g, 13.6 mmol, 1.5 eq) and PPh₃ (3.59 g, 13.6mmol, 1.5 eq) were dissolved in dry THF (40 mL) at 0° C. and allowed tostir for 1 hour. Diisopropyl azodicarboxylate (2.76 g, 13.6 mmol, 1.5eq) was added at 0° C. and reaction mixture was allowed to stir for 3hours. After completion of reaction, water was added and product wasextracted with EtOAc (100 mL×2). Organic layer was separated out, washedwith brine, dried over sodium sulphate and concentrated under reducedpressure to give crude product, which was purified by columnchromatography to afford compound 18.2 (1.8 g, 57.97%). MS (ES):m/z=339.1 [M−H]⁺

Synthesis of compound 18.3. To a solution of 18.2 (1.8 g, 5.3 mmol, 1.0eq) in HOAc (18 mL) was added iron powder (1.18 g, 21.0 mmol, 4.0 eq).Reaction mixture was then heated at 90° C. for 1 hour. After completionof the reaction, EtOAc was added to reaction mixture and reactionmixture was filtered through celite and filtrate was concentrated underreduced pressure to afford crude which was purified using columnchromatography to afford 18.3. (1.2 g, 73.1%), MS (ES): m/z 311.1[M+H]⁺.

Synthesis of 18.4. To a cooled solution of NaH (60% in mineral oil, 0.31g, 7.7 mmol, 2.0 eq) in DMF (6 mL) was added 18.3 (1.2 g, 3.8 mmol, 1.0eq) at 0° C. and allowed to stir at room temperature for 30 minutes.After completion of the reaction saturated NH₄Cl solution was added toreaction mixture and product extracted with EtOAc (200 mL×2). Organiclayer was washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to give crude product, which waspurified by column chromatography to afford compound 18.3 (0.4 g,45.11%). MS (ES): m/z 227 [M−H]⁺

Synthesis of compound 18.5. A solution of 18.4 (0.24, 1.04 mmol, 1.0 eq)in ammonium hydroxide (10 mL) was heated in hydrogenator vessel at 10psi for 24 h. After completion of the reaction, mixture was concentratedunder reduced pressure to give crude product, which was triturated withdiethyl ether to give pure 18.5 (0.09 g, 52.0%). MS (ES): m/z 166[M−H]⁺,

Synthesis of compound 18.6. To a solution of 18.5 (0.042 g 0.25 mmol,1.1 eq) in dry 1,4-dioxane (1.0 mL) was added 4.4 (0.1 g, 0.23 mmol, 1.0eq), K₂CO₃ (0.080 g, 0.04 mmol, 0.2 eq) and Xantphos (0.026 g, 0.04mmol, 0.2 eq) at room temperature and it was degassed with argon for 15minutes. To the above reaction mixture was added Pd₂(dba)₃ (0.021 g,0.02 mmol, 0.1 eq) and it was degassed again with argon for 15 minutes.Reaction mixture was heated at 110° C. for 4 hours. After completion ofthe reaction, reaction mixture was poured into water and extracted usingethyl acetate (50 mL×2). Organic layer was washed with brine solution.Organic layers were combined and dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude, which was further purified bycolumn chromatography to afford pure 18.6 (0.052 g, 40.0%). MS (ES): m/z560.2 [M+H]⁺

Synthesis of compound I-18. A solution of 18.6 (0.055 g, 0.09 mmol, 1eq) in HBr/HOAc (33%, 1 mL) was stirred at room temperature for 1 hour.After completion of reaction, reaction mixture was poured in cold water,neutralized with sodium bicarbonate and product was extracted with EtOAc(25 mL×2). Solvent was removed under reduced pressure at to get crudeproduct, which was purified by column chromatography to afford pure I-18(0.022 g, 57.8%). MS (ES): m/z 410.20 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d6):δ 9.48 (s, 1H), 8.81 (s, 1H), 8.35 (s, 1H), 7.53-7.57 (t, 1H), 7.21-7.25(t, 2H), 7.11-7.13 (d, 1H), 6.29-6.31 (d, 2H), 4.38 (s, 2H), 4.03-4.05(t, 2H), 3.23-3.29 (m, 2H), 1.89-1.92 (t, 2H),

Example 19. Synthesis of4-(6-amino-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-19

Synthesis of compound 19.2. To a solution of 4.4 (0.050 g, 0.116 mmol,1.0 eq) in 1,4-dioxane (1 mL) was added 19.1 (0.023 g, 0.174 mmol, 1.5eq) and K₂CO₃ (0.04 g, 0.29 mmol, 2.5 eq). The reaction mixture wasdegassed for 10 min. under argon atmosphere, then Pd₂(dba)₃ (0.011 g,0.012 mmol, 0.1 eq) and Xantphos (0.013 g, 0.023 mmol, 0.2 eq) wereadded, again degassed for 5 min. The reaction was then heated at 110° C.for 2 hours. After completion of reaction, reaction mixture was pouredin water and product was extracted with EtOAc. Organic layer wascombined and dried over sodium sulphate and concentrated under reducedpressure to obtain crude which was purified using column chromatographyto get pure 19.2 (0.040 g, 65.4%). MS (ES): m/z 528.5 [M+H]⁺.

Synthesis of compound I-19. Compound 19.2 (0.025 g, 0.0473 mmol, 1.0eq.) was dissolved in HBr/HOAc (1 mL) and stirred at room temperaturefor 1 hour. After completion of the reaction, mixture was poured intowater and basified with saturated bicarbonate solution was extractedwith ethyl acetate. Organic layers were combined and dried over sodiumsulphate and concentrated under reduced pressure to obtain crude whichwas purified to get pure I-19 (0.012 g, 67.2%). MS (ES): m/z 378.3[M+H]⁺ ¹H NMR (DMSO-d₆, 400 MHz): 8.95 (s, 1H), 8.27 (s, 1H), 6.49 (m,3H), 7.30 (t, 2H), 6.43 (m, 2H), 5.86 (s, 2H), 4.55 (s, 2H).

Example 20. Synthesis of4-((5-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-20

Synthesis of compoiund 20.2. To a solution of 20.1 (0.2 g, 0.985 mmol,1.0 eq) in DMSO (3 ml) was added TBAI (0.036 g, 0.0985 mmol, 0.1 eq),6-azaspiro[2.5]octane (0.131 g, 1.182 mmol, 1.2 eq), and K₂CO₃ (0.271 g,1.97 mmol, 2 eq). Reaction mixture was heated in microwave at 120° C.for 4 hours. The reaction mixture was poured into water and extractedwith EtOAc. Organic layers were combined and dried over sodium sulphateand concentrated under reduced pressure to obtain crude which waspurified by column chromatography to get pure 20.2 (0.052 g, 22.70%). MS(ES): m/z 234.27 [M+H]⁺.

Synthesis of compound 20.3. To a solution of 20.2 (0.052 g, 0.222 mmol,1.0 eq) in MeOH (5 mL) was added with 10% Pd/C (0.0052 mg) undernitrogen atmosphere. It was purged with H₂ gas for 1 h. Reaction mixturewas filtered through celite and obtained filtrate was concentrated underreduced pressure to get crude 20.3 (0.040 g) which was used as such forthe the next step, MS (ES): m/z 204.3 [M+H]⁺.

Synthesis of compound 20.4. To a solution of 4.4 (0.08 g, 0.185 mmol,1.0 eq) in 1,4-dioxane (3 mL) was added 20.3 (0.04 g, 0.204 mmol, 1.1eq) and K₂CO₃ (0.064 g, 0.464 mmol, 2.5 eq). The reaction mixture wasdegassed for 10 min. under argon atmosphere, then Pd₂(dba)₃ (0.0169 g,0.0185 mmol, 0.1 eq) and Xantphos (0.021 g, 0.0371 mmol, 0.2 eq) wereadded, again degassed for 5 min. The reaction was stirred 110° C. for 4hours. After completion of the reaction, mixture was poured into waterand product was extracted with EtOAC. Organic layers were combined,dried over sodium sulphate and concentrated under reduced pressure toobtain crude which was purified by column chromatography get pure 20.4(0.070 g, 63.10%). MS (ES): m/z 598.7 [M+H]⁺.

Synthesis of compound I-20. Compound 20.4 (0.07 g, 0.117 mmol, 1.0 eq)was dissolved in HBr/HOAc (2 ml) and stirred at room temperature for 1hour. After completion of the reaction, mixture was poured into water,basified with saturated bicarbonate solution and extracted with EtOAc.Organic layers were combined, dried over sodium sulphate andconcentrated under reduced pressure to obtain crude which was purifiedget pure I-20 (0.025 g, 47.7%). MS (ES): m/z 448.5 [M+H]⁺; ¹H NMR(DMSO-d₆, 400 MHz): 9.50 (s, 1H), 8.80 (s, 1H), 8.36 (s, 1H), 8.04 (d,1H), 7.57 (m, 1H), 7.45 (dd, 1H), 7.25 (m, 2H), 7.08 (d, 1H), 4.40 (s,2H), 3.18 (t, 4H), 1.44 (t, 4H), 0.32 (s, 4H)

Example 21. Synthesis of4-((1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-(2,6-difluoro-phenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-21

Synthesis of compound 21.1. To a solution of 19.1 (0.5 g, 3.75 mmol, 1.0equiv) and NaOAc (0.49 g, 6.00 mmol, 1 equiv) in acetic acid (5 mL) wasadded phtalic anhydride (0.667 g, 4.5 mmol, 1.2 equiv) and stirred at120° C. for 5 hours. Reaction mixture was poured into water (50 mL) andextracted with EtOAc (20 mL×3). Organic layers were combined, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.Crude was stirred in aqueous satd. NaHCO₃, filtered then dried to getpure 21.1 (0.400 g, 40.46%). MS (ES): m/z 264.3 [M+H]⁺.

Synthesis of compound 21.2. To a solution of 21.1 (0.450 g, 1.70 mmol, 1eq) in THF (4.5 mL) was added DMAP (0.020 g, 0.17 mmol, 0.1 eq) followedby di-tert-butyl dicarbonate (0.447 g, 2.05 mmol, 1.2 eq) 0° C. Reactionmixture was stirred at room temperature for 1 hour. Reaction mixture waspoured into water (50 mL) and extracted with EtOAc (20 mL×3). Organiclayers were combined, dried over sodium sulphate and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to afford 21.2 (0.50 g, 80.5%). MS (ES): m/z 364.3[M+H]⁺.

Synthesis of compound 21.3. To a solution of 21.2 (0.300 g, 0.825 mmol,1.0 eq) in EtOH (3 mL) and CH₂Cl₂ (1 mL) was added N₂H₄—H₂O (99%) (0.040mL, 0.83 mmol, 1.0 eq) and stirred at room temperature for 1 hour.Reaction mixture was poured into ice cold saturated solution of NaHCO₃(50 mL) and extracted with EtOAC (20 mL×3). Organic layers werecombined, dried over sodium sulphate and concentrated under reducedpressure to obtain crude which was purified by column chromatography tofurnish 21.3 (0.15 g, 77.9%). MS (ES): m/z 234.3 [M+H]⁺.

Synthesis of compound 21.4. To a solution of 4.4 (0.10 g 0.23 mmol, 1.0eq) in dry Dioxane (5.0 mL) was added 21.3 (0.081 g, 0.35 mmol, 1.5 eq)and K₂CO₃ (0.095 g, 0.60 mmol, 3.0 eq.) at room temperature under argonpurge for 15 minutes. To the above reaction mixture was added Pd₂(dba)₃(0.021 g, 0.023 mmol, 0.1 eq) and Xantphos (0.026 g, 0.046 mmol, 0.2 eq)under argon purge for 10 minutes. Reaction mixture was stirred at 95° C.temperature for 3 to 4 hours. After completion of the reaction, mixturewas poured into water and extracted using ethyl acetate. Organic layerswere combined, washed with brine, dried over sodium sulphate andconcentrated under reduced pressure to obtain crude. Crude was purifiedby column chromatography to get pure 21.4 (0.05 g, 34.32%). MS (ES): m/z628.6 [M+H]⁺.

Synthesis of compound I-21. A solution of 21.4 (0.025 g) in HBr/HOAcsolution (33%, 2 ml) was stirred at room temperature for 1 hour. Aftercompletion of the reaction, mixture was poured into cold water,neutralized with NaHCO₃ and extracted with ethyl acetate (50 ml×2).Solvent was removed under reduced pressure at 45° C. Resulting crude waspurified by column chromatography to furnish I-21 (0.010 g, 66.58%). MS(ES): m/z 378.35 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ 11.51 (s, 1H),9.78 (s, 1H), 8.87 (s, 1H), 8.67 (s, 1H), 7.94 (d, 1H), 7.63-7.55 (m,1H), 7.30-7.26 (m, 3H), 6.82 (d, 1H), 6.39 (s, 1H), 4.43 (s, 2H).

Example 22. Synthesis of2-(2,6-difluorophenyl)-4-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-22

Synthesis of compound 22.1. To a solution of 21.4 (0.10 g 0.159 mmol,1.0 eq) in EtOH (10.0 mL) and 1,2-Dimethoxyethane (10.0 mL) was added10% Pd/C (0.010 mg) under nitrogen atmosphere. Suspension was purgedwith hydrogen for 12 h. Reaction mixture was filtered through celite andobtained filtrate was concentrated under reduced pressure to get crude22.1 (0.090 g, 89.72%) which was used as such for the next step, MS(ES): m/z 630.7 [M+H]⁺.

Synthesis of compound I-22. A solution of 22.1 (0.09 g) in HBr/HOAcsolution (33%, 2 ml) was stirred at room temperature for 1 hour. Aftercompletion of the reaction, mixture was poured into cold water,neutralized with NaHCO₃ and product was extracted with EtOAc (50 ml×2).Solvent was concentrated under reduced pressure to get crude which wastriturated using Et₂O (2.0 mL) and MeOH (0.2 mL) to furnish I-22. (0.05g, 92.2%). MS (ES): m/z 380.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 9.46(s, 1H), 8.81 (s, 1H), 8.34 (s, 1H), 7.56 (t, 1H), 7.27-7.23 (m, 3H),6.52 (s, 1H), 6.12 (d, 1H), 4.39 (s, 2H), 3.46 (t, 2H), 2.91 (t, 2H).

Example 23. Synthesis of2-(2,6-difluorophenyl)-4-((3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-23

Synthesis of compound 23.2. To a solution of 23.1 (0.97 g 4.1 mmol, 1.0eq.) in dry CH₂Cl₂ (6.0 mL) was added anhydrous AlCl₃ (1.66 g, 12.5mmol, 3.0 eq) at 0° C. under argon atmosphere. The reaction mixture wasstirred at 50° C. for 16 hours. After completion of the reaction,mixture was poured into diluted HCl to adjust pH to 4, and extractedusing CH₂Cl₂. Organic layer was washed with brine and dried over sodiumsulfate. Organic layer was concentrated under reduced pressure and crudewas purified by column chromatography to afford pure 23.2 (0.76 g,83.39%). MS (ES): m/z 219.1 [M+H]⁺.

Synthesis of compound 23.3. To a solution of 23.2 (0.76 g, 3.57 mmol,1.0 eq) in acetone (8 mL) were added K₂CO₃ (1.20 g, 8.71 mmol, 2.5 eq)and NaI (0.575 g, 3.83 mmol, 1.1 eq) at room temperature and stirred for20 minutes. To the mixture 3-Bromo-2-methylpropane (0.611 g, 4.53 mmol,1.3 eq) was added and reaction was heated at reflux temperature for 2hours. After completion of the reaction, mixture was diluted with waterand extracted with EtOAc. Organic layer was dried over sodium sulphateand concentrate under reduced pressure at 45° C. Crude was purified bycolumn chromatography to afford 23.3 (0.60 g, 63.25%). MS (ES):m/z=273.1 [M+H]⁺.

Synthesis of compound 23.4. To a solution of 23.3 (0.6 g, 2.20 mmol. 1.0eq.) in dry DMF (15.0 ml) was added Et₃NI (0.38 g, 2.4 mmol, 1.09 eq),Sodium formate (0.156 g, 2.40 mmol, 1.09 eq) and NaOAc (0.44 g, 5.51mmol, 2.5 eq). Reaction mixture was degassed for 10 min and Palladiumacetate (0.048 g, 0.22 mmol, 0.1 eq) was added and again reactionmixture degassed for 10 min. Reaction mixture was heated at 70° C.overnight. After completion of the reaction, mixture was poured in coldwater and product was extracted with EtOAc. Organic layer was washedwith brine, dried over sodium sulphate. Solvent was removed underreduced pressure and crude was purified by column chromatography toafford pure 23.4 (0.34 g, 79.8%). MS (ES): m/z 194.3 [M+H]⁺.

Synthesis of compound 23.5. To a suspension of Pd/C (0.034 g) in MeOH(10 mL) was added 23.4 (0.340 g, 1.76 mmol, 1.0 eq) under nitrogenatmosphere. Above reaction mixture was purged with Eh (gas) at roomtemperature for 1 hour. After completion of the reaction, reactionmixture was filter through celite. Solvent was removed under reducedpressure to afford 23.5 (0.250 g, 87.0%). MS (ES): m/z 164.4 [M+H]⁺.

Synthesis of 23.6. To a solution of 1.1 in DMSO (5.0 mL) were added 24.5(0.075 g, 0.46 mmol, 1.0 eq.) and DIPEA (0.149 mg, 1.16 mmol, 2.5 eq.)at room temperature. Reaction was heated at 70° C. for 30 minutes. Aftercompletion of the reaction, mixture was poured into water and extractedusing EtOAc. Organic layer was washed with by brine, dried over sodiumsulfate and concentrated under reduced pressure. Crude was purified bycolumn chromatography to afford pure 23.6 (0.151 g, 58.37%). MS (ES):m/z 559.6 [M+H]⁺

Synthesis of compound I-23. A solution of 23.6 (0.151 g) in TFA (6 mL)was heated at 70° C. for 8 hrs. After completion of the reaction,mixture was concentrated under reduced pressure at 45° C. Obtainedresidue was poured in cold water, neutralized with NaHCO₃ and productwas extracted with EtOAc. Solvent was removed under reduced pressure toget crude which was purified by preparative TLC to afford pure I-23 (34mg, 30.8%). MS (ES): m/z 409.4 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ 8.99(s, 1H), 8.89 (s, 1H), 7.62-7.58 (m, 1H), 7.40 (s, 1H), 7.30-7.26 (t,2H), 7.17-7.15 (d, 1H), 7.10-7.08 (s, 1H), 4.47 (s, 2H), 4.21 (s, 2H),1.27 (s, 6H).

Example 24. Synthesis of compound4-((5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-24

Synthesis of compound 24.1. To a solution of 20.1 (0.6 g, 2.95 mmol, 1.0eq) in 1,4-dioxane (10 ml) was added 2-oxa-7-azaspiro[3.5]nonane (0.641g, 2.95 mmol, 1.0 eq) and K₂CO₃ (1.2 g, 8.86 mmol, 3.0 eq). The reactionmixture was degassed for 10 min. using argon, then Pd₂(dba)₃ 0.063 g,0.29 mmol, 0.1 eq) and Xantphos (0.341 g, 0.59 mmol, 0.2 eq) were added,again degassed for 5 minutes. Reaction was stirred at 120° C. for 4hours. After completion of the reaction, reaction mixture was pouredinto water and product was extracted with EtOAc. Organic layers werecombined, dried over sodium sulphate and concentrated under reducedpressure to obtain crude which was purified to get pure 24.1 (0.210 g,28.5%). MS (ES): m/z 250.2 [M+H]⁺.

Synthesis of compound 24.2. A solution of 24.1 (0.210 g, 0.84 mmol, 1.0eq) in MeOH (5 mL) was added 10% Pd/C (0.050 g) under nitrogenatmosphere. It was purged with H₂ gas for 1 hour. Reaction mixture wasfiltered through celite and obtained filtrate was concentrated underreduced pressure to get crude 24.2 (0.130 g, 70.37%) which was used assuch for the next step, MS (ES): m/z 220.2 [M+H]⁺.

Synthesis of compound I-24. To a solution of 24.3 (0.050 g, 0.15 mmol,1.0 eq) in 1,4-dioxane (3 mL) was added 1.2 (0.027 g, 0.12 mmol, 0.8 eq)and Sodium t-butoxide (0.029 g, 0.30 mmol, 2.0 eq). The reaction mixturewas degassed for 10 minutes under argon atmosphere, thenChloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.022 g, 0.030 mmol, 0.2 eq) was added, again degassed for 5 min. Thereaction was stirred at 100° C. for 8 hours. After completion of thereaction, mixture was poured into water and product was extracted withEtOAC. Organic layers were combined, dried over sodium sulphate andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to get pure I-24 (0.011 g, 10.4%). MS (ES): m/z464.4 [M+H]⁺. 1H NMR (CDCl₃, 400 MHz): 9.41 (s, 1H), 8.54 (s, 1H), 8.04(s, 1H), 7.43-7.30 (m, 2H), 7.06-7.01 (m, 2H), 6.92-6.90 (d, 1H), 4.54(s, 2H), 4.49 (s, 4H), 3.09-3.06 (t, 4H), 2.05-2.03 (t, 4H).

Example 25. Synthesis of4-((5-(l-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-25

Synthesis of compound 25.2. To a solution of Trimethyl sulphoxoniumiodide (22.09 g, 100.4 mmol, 4.0 eq) in t-butanol (150 mL) was addedpotassium tert-butoxide (11.24 g, 100.4 mmol, 4.0 eq). Reaction wasstirred at 50° C. for 1 h. Then 25.1 (5 g, 25 mmol, 1 eq) was added at50° C. and allowed to stir for 2 days. After completion of the reaction,mixture was concentrated under reduced pressure. Water was added toreaction mixture and product was extracted with Et₂O. Organic layer wascombined and dried over Na₂SO₄ and concentrated under reduced pressureto obtain crude which was purified by tituration in hexane to give pure25.2 (3.6 g, 63.11%). MS (ES): m/z 227.30 [M+H]⁺.

Synthesis of compound 25.3. To compound 25.2 (3.6 g, 15.78 mmol, 1.0 eq)TFA was added. The reaction was stirred for 2 h. After completion of thereaction, mixture was concentrated under reduced pressure. The reactionmixture was neutralized using amberlyst resin in methanol. Reactionmixture was concentrated under reduced pressure to get crude 25.3 (2.0g, 99.3%) which was used as such for the next step, MS (ES): m/z 127.19[M+H]⁺.

Synthesis of compound 25.4. To a solution of 20.1 (2.0 g, 9.85 mmol, 1eq.) in DMSO (18 ml) was added compound 25.3 (1.87 g, 14.77 mmol, 1.5eq), tetra butyl ammonium iodide (0.363 g, 0.98 mmol, 0.1 eq), and K₂CO₃(4.078 g, 29.55 mmol, 3.0 eq). Reaction mixture was heated at 90° C. for2 h. After completion of the reaction, mixture was poured into water togive solid product. The product was extracted with EtOAC. Organic layerswere combined and dried over sodium sulphate and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to furnish 25.4 (0.37 g, 10.1%). MS (ES): m/z 249.27[M+H]⁺.

Synthesis of compound 199.5. To a solution of 199.4 (0.370 g, 1.48 mmol,1.0 eq) in MeOH (15 mL) was added 10% Pd/C (0.060 g) under nitrogenatmosphere. It was purged with hydrogen for 1 hours. Reaction mixturewas filtered through celite and obtained filtrate was concentrated underreduced pressure to get crude 199.5 (0.263 g, 98.88%) which was used assuch for the next step. MS (ES): m/z 219.29 [M+H]⁺.

Synthesis of compound 24.3. Compound 4.4 (1.0 g, 2.32 mmol, 1.0 eq) wasdissolved in H Br/HOAc (10 ml) and stirred at room temperature for 4 h.After completion of the reaction, mixture was poured into water andbasified with saturated bicarbonate solution and extracted with EtOAc.Organic layers were combined, dried over sodium sulphate andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to get pure 24.3 (0.630 g, 83.49%). MS (ES):m/z 325.11 [M+H]⁺.

Synthesis of compound I-25. To a solution of compound 24.3 (0.250 g,0.768 mmol, 1.0 eq.) in 1,4-dioxane were added compound 25.5 (0.168 g,0.768 mmol, 1.0 eq) and K₃PO₄ (0.326 g, 1.53 mmol, 2.0 eq). The reactionmixture was degassed for 15 minutes. Pre-catalyst Xantphos (0.111 g,0.153 mmol, 0.2 eq) was added to the reaction mixture and reaction wasfurther degassed for 10 minutes. The reaction mixture was heated at 100°C. for 20 minutes. After completion of the reaction, mixture was pouredinto water and product was extracted with EtOAC. Organic layers werecombined, dried over sodium sulphate and concentrated under reducedpressure to obtain crude which was purified by column chromatography andpreparative HPLC to furnish I-25 (0.007 g, 2.92%). MS (ES): m/z 463.49[M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): 9.48 (s, 1H), 8.80 (s, 1H), 8.36 (s,1H), 8.02-8.01 (d, 2H), 7.59-7.54 (m, 1H), 7.46-7.43 (dd, 1H), 7.27-7.23(t, 3H), 7.10-7.08 (d, 1H), 5.50 (s, 1H), 4.48-4.46 (t, 1H), 4.40 (s,2H), 3.60 (s, 2H), 3.52-3.44 (m, 2H), 3.31-3.28 (m, 2H), 2.16 (s, 4H).

Example 26. Synthesis of2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-N-ethyl-4,4,4-trifluoro-2-hydroxybutanamide,I-26

Synthesis of compound 26.1. To a solution of 1.1 (0.06 g, 0.137 mmol,1.0 eq) in Butanol (3 mL) was added2-(4-aminophenyl)-N-ethyl-3-fluoro-2-hydroxypropanamide compound with113,311-prop-1-yne (1:1) (0.038 g, 0.137 mmol, 1.0 eq) and DIPEA (0.07ml, 0.411 mmol, 3.0 eq). The reaction was then heated at 85° C. for 2 h.After completion of the reaction, mixture was poured in water andproduct was extracted with ethyl acetate. Organic layers were combined,dried over sodium sulphate and concentrated under reduced pressure toobtain crude 26.1 which was used in next step without furtherpurification. 1.1 (0.07 g, 64.3%). MS (ES): m/z 671.6 [M+H]⁺.

Synthesis of compound I-26. A solution of 26.1 (0.12 g, 0.214 mmol, 1.0eq) in HBr/HOAc (3 mL) was stirred at room temperature for 2 h. Uponcompletion reaction was quenched with water and extracted with EtOAc.Organic layer was washed with satd. NaHCO₃ solution. Combined organiclayers were washed with brine, dried over sodium sulphate andconcentrated under reduced pressure to afford crude, which was purifiedby column chromatography to furnish I-26 (0.053 g, 97.5%). MS (ES): m/z521.6 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.82 (s, 1H), 7.83-7.81 (d,2H), 7.60-7.57 (d, 2H), 7.48-7.41 (m, 1H), 7.08-7.02 (m, 2H), 6.82-6.79(m, 1H), 6.25 (s, 1H), 4.56 (s, 2H), 3.51-3.16 (m, 4H), 1.14-1.11 (t,3H).

Example 27. Synthesis of(S)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-N-ethyl-4,4,4-trifluoro-2-hydroxybutanamide,I-27

Compound I-27 was prepared by chiral separation of compound I-26. MS(ES): m/z 521.3 [M+H]⁺, ¹H NMR (400 MHz, CDCl₃): δ 8.78 (s, 1H),7.84-7.81 (d, 2H), 7.59-7.57 (d, 2H), 7.45-7.42 (m, 1H), 7.07-7.03 (m,2H), 6.83-6.80 (m, 1H), 6.33 (s, 1H), 4.54 (s, 2H), 3.44-3.17 (m, 3H),2.87-2.81 (m, 1H), 1.14-1.11 (t, 3H).

Example 28. Synthesis of(R)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-N-ethyl-4,4,4-trifluoro-2-hydroxybutanamide,I-28

Compound I-28 was prepared by chiral separation of compound I-26. MS(ES): m/z 521.3 [M+H]⁺, ¹H NMR (400 MHz, CDCl₃): δ 8.78 (s, 1H),7.84-7.81 (d, 2H), 7.59-7.57 (d, 2H), 7.45-7.42 (m, 1H), 7.07-7.03 (m,2H), 6.83-6.80 (m, 1H), 6.33 (s, 1H), 4.54 (s, 2H), 3.44-3.17 (m, 3H),2.87-2.81 (m, 1H), 1.14-1.11 (t, H).

Example 29. Synthesis of2-(2,6-difluorophenyl)-4-((4-(2,2,2-trifluoro-1-hydroxy-ethyl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-29

Synthesis of compound 29.2. To a solution of 29.1 (1 g, 6.6 mmol, 1.0eq) in THF (3 ml) was added trimethyl (trifluoromethyl) silane (1.41 g,9.9 mmol, 1.5 eq) at 0° C. Tetrabutyl ammonium fluoride (0.132 ml, 0.13mmol, 0.02 eq) was added at 0° C. and allowed to stir for 10 minutes andthen at room temperature for 2 hours. Reaction mixture was poured into 3N HCl and product was extracted with CH₂Cl₂. Organic layers werecombined, dried over sodium sulphate and concentrated under reducedpressure to obtain crude which was purified by column chromatography toget pure 29.2 (1.1 g, 75.17%). MS (ES): m/z 221.14 [M+H]⁺.

Synthesis of compound 29.3. To a solution of 29.2 (1.1 g, 5.0 mmol, 1.0eq) in MeOH (10 ml) was added 10% Pd/C (0.2 g) under nitrogenatmosphere. It was purged with hydrogen for 1 hour. Reaction mixture wasfiltered through celite and obtained filtrate was concentrated underreduced pressure to get crude 29.3 (0.820 g, 86.2%) which was used assuch for the next step, MS (ES): m/z 191.15 [M+H]⁺.

Synthesis of compound 29.4. To a solution of 1.1 (0.300 g, 0.697 mmol,1.0 eq) in n-Butanol (4 ml) was added 29.3 (0.146 g, 0.767 mmol, 1.1 eq)and DIPEA (0.27 g, 2.093 mmol, 3.0 eq). Reaction was stirred at 110° C.for 2 hours. After completion of the reaction, mixture was poured intowater and product was extracted with EtOAc. Organic layers werecombined, dried over sodium sulphate and concentrated under reducedpressure to obtain crude which was purified by column chromatography tofurnish 29.4 (0.320 g, 78.53%). MS (ES): m/z 586.52 [M+H]⁺.

Synthesis of compound I-29. Compound 29.4 (0.320 g, 0.545 mmol, 1.0 eq)was dissolved in HBr/HOAc (5 ml) and stirred at room temperature for 2hours. After completion of the reaction, mixture was poured into water,basified with satd. NaHCO₃ solution and extracted with EtOAc. Organiclayers were combined, dried over sodium sulphate and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to furnish I-26 (0.125 g, 52.52%). MS (ES): m/z 436.34[M+H]⁺, ¹H NMR (MeOD, 400 MHz): 7.87-7.85 (d, 2H), 7.60-7.52 (m, 1H),7.50-7.48 (d, 2H), 7.18-7.14 (m, 2H), 5.05-4.99 (s, 2H), 4.52 (s, 1H).

Example 30. Synthesis of(S)-2-(2,6-difluorophenyl)-4-((4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-30

Compound I-30 was prepared by chiral separation of compound I-29. MS(ES): m/z 436.34 [M+H]⁺, ¹H NMR (400 MHz, MeOD): δ 7.87-7.85 (d, 2H),7.58-7.53 (m, 3H), 7.50-7.48 (d, 2H), 7.18-7.14 (m, 2H), 4.52 (s, 1H).

Example 31. Synthesis of(R)-2-(2,6-difluorophenyl)-4-((4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-31

Compound I-31 was prepared by chiral separation of compound I-29. MS(ES): m/z 436.34 [M+H]⁺, ¹H NMR (400 MHz, MeOD): δ 7.87-7.85 (d, 2H),7.60-7.53 (m, 1H), 7.50-7.48 (d, 2H), 7.18-7.14 (m, 2H), 4.64 (s, 2H),4.52 (s, 1H).

Example 32. Synthesis of2-amino-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)propanoicacid, I-32

Synthesis of compound 32.1. To a solution of 1.1 (0.073 g, 0.170 mmol,1.0 eq) in Butanol (5 mL) were added methyl2-(4-aminophenyl)-2-((tert-butoxycarbonyl)-amino)propionate (0.050 g,0.170 mmol, 1.0 eq) and DIPEA (0.09 ml, 0.510 mmol, 3.0 eq). Thereaction was stirred at 100° C. for 2 hours. After completion of thereaction, mixture was poured into water and product was extracted withEtOAc. Organic layers were combined, dried over sodium sulphate andconcentrated under reduced pressure to obtain crude 32.1 (0.070 g,60.04%) which was used in next step without further purification. MS(ES): m/z 690.72 [M+H]⁺.

Synthesis of compound 32.2. Solution of 32.1 (0.070 g, 0.106 mmol, 1.0eq) in HBr/HOAc (3 mL) was stirred at room temperature for 2 hr. Uponcompletion, water was added and product was extracted with EtOAc.Organic layers were washed with satd. NaHCO₃ solution. Combined organiclayers were washed with brine, dried over sodium sulphate andconcentrated under reduced pressure afford crude, which was purified bycolumn chromatography to furnish 32.2 (0.030 g, 67.27%). MS (ES): m/z440.42 [M+H]⁺.

Synthesis of compound I-32. Compound 32.2 (0.030 g, 0.068 mmol, 1.0 eq)was dissolved in MeOH (2 ml). 2N NaOH (0.090 ml, 0.204 mmol, 3.0 eq) wasadded and stirred at room temperature for 1 hr. After completion ofreaction, mixture was concentrated under reduced pressure. Crudecompound was purified by prep HPLC to get pure I-32 (0.008 g, 24.4%). MS(ES): m/z 425.40 [M+H]⁺, ¹H NMR (MeOD, 400 MHz): 7.88-7.85 (m, 2H),7.58-7.53 (m, 3H), 7.16-7.12 (m, 2H), 4.51 (s, 2H), 1.88 (s, 3H).

Example 33. Synthesis of2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxy-propan-2-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-33

Synthesis of compound 33.2. To a solution of 33.1 (1 g, 6 mmol, 1.0 eq)in THF (15 ml) was added trimethyl (trifluoromethyl) silane (1.3 g, 9mmol, 1.5 eq) and cooled at 0° C. Tetrabutyl ammonium fluoride (0.132ml, 0.13 mmol, 0.02 eq) was added at 0° C. and allowed to stir for 10minutes and then at room temperature for 2 hours. Reaction mixture waspoured in 3 N HCl and product was extracted with EtOAc. Organic layerswere combined, dried over sodium sulphate and concentrated under reducedpressure to obtain crude which was purified by column chromatography toget pure 33.2 (1 g, 70.2%). MS (ES): m/z 235.16 [M+H]⁺.

Synthesis of compound 33.3. To a solution of 33.2 (0.3 g, 1.2 mmol, 1.0eq) in MeOH (10 ml) was added 10% Pd/C (0.2 g) under nitrogenatmosphere. It was purged with hydrogen for 1 hour. Reaction mixture wasfiltered through celite and obtained filtrate was concentrated underreduced pressure to get crude 33.3 (0.250 g, 95.51%) which was used assuch for the next step, MS (ES): m/z 205.18 [M+H]⁺.

Synthesis of compound 33.4. To a solution of 1.1 (0.100 g, 0.23 mmol,1.0 eq) in n-Butanol (5 ml) was added 33.3 (0.047 g, 0.23 mmol, 1.0 eq)and DIPEA (0.089 g, 0.69 mmol, 3.0 eq). Reaction mixture was stirred at90° C. for 3 hours. After completion of the reaction, n-butanol wasremoved under high vacuum to obtain crude material 33.4 (0.100 g,71.99%). MS (ES): m/z 600.18 [M+H]⁺.

Synthesis of compound I-33. Compound 33.4 (0.100 g, 0.166 mmol, 1.0 eq)was dissolved in HBr/HOAc (3 ml) and stirred at room temperature for 1hour. After completion of the reaction, mixture was poured into waterand basified with satd. NaHCO₃ and product was extracted with EtOAc.Organic layers were combined, dried over sodium sulphate andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to get pure I-33 (0.050 g, 66.7%). MS (ES): m/z450.37 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 9.13 (s, 1H), 8.92 (s, 1H),7.80-7.78 (d, 2H), 7.56-7.54 (m, 3H), 7.29-7.27 (m, 2H), 6.55 (d, 1H),4.49 (s, 2H), 1.67 (s, 3H).

Example 34. Synthesis of(S)-2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxy-propan-2-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,I-34

Compound I-34 was prepared by chiral separation of compound I-33 MS(ES): m/z 450.37 [M+H]⁺, ¹H NMR (400 MHz, MeOD): δ 7.85-7.80 (m, 2H),7.63-7.52 (m, 3H), 7.18-7.13 (m, 2H), 4.52 (s, 2H), 1.73 (s, 3H).

Example 35. Synthesis of(R)-2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxy-propan-2-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-oneI-35

Compound I-35 was prepared by chiral separation of compound I-33 MS(ES): m/z 450.37 [M+H]⁺, ¹H NMR (400 MHz, MeOD): δ 7.85-7.83 (m, 2H),7.61-7.54 (m, 3H), 7.18-7.14 (m, 2H), 4.52 (s, 2H), 1.73 (s, 3H).

Example 36. Synthesis of4-((5-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-36

Synthesis of compound 36.1. To a solution of 20.1 (0.400 g, 1.97 mmol,1.0 eq) in 1,4-dioxane (10 mL) were added 1-oxa-6-azaspiro[3.5]nonane(0.406 g, 2.36 mmol, 1.2 eq) and Cs₂CO₃ (1.92 g, 5.91 mmol, 3.0 eq). Thereaction mixture was degassed for 10 min. using argon, then Pd₂(dba)₃(0.180 g, 0.197 mmol, 0.1 eq) and2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.154 g, 0.394mmol, 0.2 eq) were added, and again degassed for 5 min. Reaction wasstirred at 110° C. for 4 h. After completion of the reaction, mixturewas poured into water and product was extracted with EtOAc. Organiclayers were combined and dried over sodium sulphate and concentratedunder reduced pressure to obtain crude which was purified by columnchromatography to furnish 36.1 (0.36 g, 73.3%). MS (ES): m/z 250.6[M+H]⁺.

Synthesis of compound 36.2. To a solution of 36.1 (0.360 g, 1.44 mmol,1.0 eq) in MeOH (5 mL) was added 10% Pd/C (0.350 g) under nitrogenatmosphere. It was purged with hydrogen for 1 hour. Reaction mixture wasfiltered through celite and obtained filtrate was concentrated underreduced pressure to get crude 36.2 (0.300 g, 94.73%) which was used assuch for the next step, MS (ES): m/z 220.23 [M+H]⁺.

Synthesis of compound I-36. To a solution of 24.3 (0.400 g, 1.23 mmol,1.0 eq) in 1,4-dioxane (3 mL) was added 36.2 (0.269 g, 1.23 mmol, 1.0eq) and K₃PO₄ (0.52 g, 2.46 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 min. using argon, thenchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)(0.182 g, 0.25 mmol, 0.2 eq) was added, again degassed for 5 minutes.Reaction was then stirred at 100° C. for 1 hour. After completion of thereaction, mixture was poured into water and product was extracted withEtOAc. Organic layers were combined, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude which was purified by columnchromatography to furnish I-36 (0.163 g, 28.6%). MS (ES): m/z 463.6[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 9.51 (s, 1H), 8.81 (s, 1H), 8.39(s, 1H), 8.09 (s, 1H), 7.64-7.49 (m, 2H), 7.34-7.23 (m, 2H), 7.10-7.08(d, 1H), 4.48-4.39 (m, 1H), 4.38 (s, 2H), 3.43-3.40 (m, 1H), 3.12-3.01(m, 2H), 2.90-2.86 (m, 1H), 2.43-2.28 (m, 3H), 1.87-1.83 (m, 1H),1.73-1.62 (m, 2H), 1.56-1.50 (m, 1H).

Example 37. Synthesis of(R)-4-((5-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-37

Compound I-37 was prepared by chiral separation of compound I-36. MS(ES): m/z 463.3 [M+H]⁺, ¹H NMR (400 MHz, MeOD): δ 8.45 (s, 1H), 8.10 (s,1H), 7.56-7.50 (m, 2H), 7.16-7.12 (m, 2H), 7.06-7.04 (d, 1H), 4.65-4.55(m, 2H), 4.47 (s, 2H), 3.33-3.31 (m, 2H), 3.09-3.07 (m, 2H), 2.55-2.45(m, 2H), 1.91-1.86 (m, 2H), 1.70-1.66 (m, 2H).

Example 38. Synthesis of(S)-4-((5-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-38

Compound I-38 was prepared by chiral separation of compound I-36. MS(ES): m/z 463.3 [M+H]⁺, ¹H NMR (400 MHz, MeOD): δ 8.45 (s, 1H), 8.10 (s,1H), 7.56-7.50 (m, 2H), 7.16-7.12 (m, 2H), 7.06-7.04 (d, 1H), 4.65-4.55(m, 2H), 4.47 (s, 2H), 3.33-3.31 (m, 2H), 3.09-3.07 (m, 2H), 2.55-2.45(m, 2H), 1.91-1.86 (m, 2H), 1.70-1.66 (m, 2H).

Example 39. Synthesis of2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-2,4-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one,I-39

Synthesis of compound 39.2. To a solution of 39.1 (5.0 g, 23.92 mmol,1.0 eq) in THF (50 ml) was added Mel (3.73 g, 26.31 mmol, 1.1 eq.) and18-crown-6 (1.57 g, 59.80 mmol, 0.25 eq.). The reaction mixture wascooled to −78° C. and potassium t-butoxide (2.94 g, 26.31 mmol, 1.1 eq)was added. Reaction was stirred at room temperature for 6 hours. Aftercompletion of reaction, NH₄Cl was added at −78° C. Product was extractedwith EtOAc. Organic layers were combined and dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to furnish 39.2 (4.5 g, 84.34%). MS (ES): m/z223.23 [M+H]⁺.

Synthesis of compound 39.3. To a solution of compound 39.2 (4.5 g, 20.17mmol, 1.0 eq) in ethanol (40 ml) was added NaOH (1.614 g, 40.35 mmol, 2eq.) and water (10 ml). Reaction was stirred at room temperature for 2hours. After completion of the reaction, solvent was evaporated underreduced pressure and water was added. Dilute HCl was added to acidifythe reaction mixture. The product was extracted with ethyl acetate.Organic layers were combined and dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude which was purified by columnchromatography to furnish 39.3 (3.1 g, 78.8%). MS (ES): m/z 195.17[M+H]⁺.

Synthesis of compound 39.4. To a solution of 2-fluoro-N-methylaniline(1.98 g, 15.89 mmol, 1 eq.) in CH₂Cl₂ (50 ml) was added compound 39.3(3.1 g, 15.8 mmol, 1 eq). Further DMAP (0.386 g, 3.168 mmol, 0.2 eq) wasadded and the reaction was cooled at 0° C. Dicyclohexyl carbodiimide(3.91 g, 19.00 mmol, 1.2 eq) was added at 0° C. and the reaction wasstirred at room temperature for 24 hours. After completion of thereaction, mixture was filtered through celite and the filtrate wasconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to furnish 39.4 (0.330 g, 10.76%). MS (ES): m/z302.31 [M+H]⁺.

Synthesis of compound 39.5. To a solution of compound 39.4 (0.280 g,0.927 mmol, 1 eq.) in DMF (10 ml) was added copper (II) chloride (0.273g, 2.039 mmol, 2.2 eq.) and sodium t-butoxide (0.45 g, 4.64 mmol, 5.0eq.) Reaction was stirred at 80° C. for 24 hours. After completion ofthe reaction, mixture was poured into water and brine solution was addedto it. Product was extracted with EtOAc. Organic layers were combined,dried over sodium sulphate and concentrated under reduced pressure toobtain crude which was further purified by column chromatography to getpure 39.5 (0.069 g, 24.9%). MS (ES): m/z 298.30 [M+H]⁺.

Synthesis of compound 39.6. To a Pd/C (20 mg) suspension in methanol (2ml) was added 39.5 (0.069 mg, 0.231 mmol, 1.0 eq). Hydrogen gas waspurged into the reaction mixture for 2 hours at ambient temperature.After completion of the reaction, mixture was filtered through celiteand washed with methanol. The filtrate was evaporated under reducedpressure to obtain crude which was purified by column chromatography toget pure 9.5 (0.059 g, 95.06%). MS (ES): m/z 268.32 [M+H]⁺.

Synthesis of compound 39.7. To a solution of 1.1 (0.100 g, 0.234 mmol,1.0 eq.) in n-butanol (1 mL) were added compound 39.6 (0.059 g, 0.234mmol, 1.0 eq.) and DIPEA (0.075 g, 0.58 mmol, 2.5 eq.). Reaction wasstirred at 80° C. for 3 hours. After completion of the reaction, mixturewas poured into water. The product was extracted with EtOAc. Organiclayers were combined, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude which was purified by column chromatography toget pure 221.6 (0.130 g, 84.58%). MS (ES): m/z 663.68 [M+H]⁺.

Synthesis of compound I-39. Compound 39.7 (0.130 g, 0.195 mmol, 1.0 eq)was dissolved in HBr/HOAc (2 mL) and stirred at room temperature for 1hour. After completion of the reaction, mixture was poured into waterand basifled with satd. NaHCO₃ and extracted with EtOAc Organic layerswere combined, dried over Na₂SO₄ and concentrated under reduced pressureto obtain crude which was purified by column and preparative HPLC tofurnish I-39 (0.060 g, 59.65%). MS (ES): m/z 513.50 [M+H]⁺, ¹H NMR(DMSO-d₆, 400 MHz): δ 9.05 (s, 1H), 8.91 (s, 1H), 7.71-7.69 (d, 2H),7.63-7.59 (m, 1H), 7.30-7.25 (m, 4H), 7.13-7.11 (m, 1H), 7.05-7.03 (m,1H), 6.99-6.95 (m, 2H), 4.46 (s, 2H) 1.77 (s, 3H).

Example 40. Synthesis of(S)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-2,4-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one,I-40

Compound I-40 was prepared by chiral separation of compound I-39. MS(ES): m/z 513.50 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 9.05 (s, 1H), 8.90(s, 1H), 7.71-7.69 (d, 2H), 7.63-7.59 (m, 1H), 7.30-7.25 (m, 4H),7.13-7.11 (m, 1H), 7.05-7.03 (m, 1H), 6.99-6.95 (m, 2H), 4.45 (s, 2H)1.77 (s, 3H).

Example 41. Synthesis of(R)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)-2,4-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one,I-41

Compound I-41 was prepared by chiral separation of compound I-39. MS(ES): m/z 513.50 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 9.05 (s, 1H), 8.90(s, 1H), 7.71-7.69 (d, 2H), 7.62-7.59 (m, 1H), 7.30-7.25 (m, 4H),7.13-7.03 (m, 2H), 6.99-6.95 (m, 2H), 4.46 (s, 2H) 1.77 (s, 3H).

Example 42. Synthesis of2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-42

Synthesis of compound 42.1. To a solution of 4.4 (0.150 g, 0.348 mmol,1.0 eq) in 1,4-dioxane (8 mL) was added 33.3 (0.071 g, 0.348 mmol, 1.0eq) and K₂CO₃ (0.144 g, 1.04 mmol, 3 eq). The reaction mixture wasdegassed for 10 min. using argon, then Pd₂(dba)₃ (0.031 g, 0.034 mmol,0.1 eq) and Xantphos (0.040 g, 0.069 mmol, 0.2 eq) were added, and againdegassed for 5 minutes. Reaction was stirred at 90° C. for 3 hours.After completion of the reaction, mixture was poured into water andproduct was extracted with EtOAc. Organic layers were combined, driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudewhich was purified by column chromatography to furnish 42.1 (0.120 g,57.5%). MS (ES): m/z 599.46 [M+H]⁺.

Synthesis of compound I-42. Solution of 42.1 (0.120 g, 0.200 mmol, 1.0eq) in HBr/HOAc (3 mL) was stirred at ambient temperature for 1 h. Aftercompletion of reaction pH was adjusted to 7 by addition of NaHCO₃solution. The product was extracted with EtOAc. Combined organic layerswere washed with brine, dried over sodium sulphate and concentratedunder reduced pressure to afford crude, which was purified by columnchromatography to furnish I-42 (0.065 g, 72.3%). MS (ES): m/z 449.38[M+H]⁺. NMR (DMSO-d₆, 400 MHz): δ 9.07 (s, 1H), 8.75 (s, 1H), 7.61-7.59(d, 2H), 7.57-7.49 (m, 1H), 7.40-7.38 (d, 2H), 7.23-7.18 (m, 2H), 7.11(s, 1H), 6.59 (s, 1H), 4.40 (s, 2H), 1.68 (s, 3H).

Example 43. Synthesis of(S)-2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-43

Compound I-43 was prepared by chiral separation of I-42. MS (ES): m/z449.38 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ 9.15 (s, 1H), 8.78 (s, 1H),7.62-7.60 (d, 2H), 7.56-7.51 (m, 1H), 7.41-7.39 (d, 2H), 7.24-7.20 (m,2H), 7.12 (s, 1H), 6.60 (s, 1H), 4.24 (s, 2H), 1.68 (s, 3H).

Example 44. Synthesis of(R)-2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxy-propan-2-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-44

Compound I-44 was prepared by chiral separation of I-42. MS (ES): m/z449.38 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ 9.15 (s, 1H), 8.77 (s, 1H),7.62-7.59 (d, 2H), 7.56-7.51 (m, 1H), 7.41-7.38 (d, 2H), 7.24-7.19 (m,2H), 7.12 (s, 1H), 6.59 (s, 1H), 4.42 (s, 2H), 1.68 (s, 3H).

Example 45. Synthesis of(S)-2-amino-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)propanoicacid hydrochloride, I-45

Synthesis of compound 45.2. To a solution of 45.1 (0.500 g, 1.23 mmol,1.0 eq) in MeOH (10 ml) was added 10% Pd/C (0.2 g) under nitrogen. Itwas purged with H₂ gas at ambient temperature for 24 h. Reaction mixturewas filtered through celite, washed with methanol and obtained filtratewas concentrated under reduced pressure to get crude which was purifiedby column chromatography to furnish 232.1 (0.26 g, 71.2%) MS (ES): m/z294.35 [M+H]⁺.

Synthesis of compound 45.3. Compound 45.2 was prepared by chiralseparation of 232.1 (0.085 g), MS (ES): m/z 294.35 [M+H]⁺, ¹H NMR (400MHz, DMSO-d₆): δ 7.07-7.04 (d, 2H), 6.50-6.48 (d, 2H), 5.10 (s, 2H),3.55 (s, 3H), 1.67 (s, 3H), 1.36 (s, 9H).

Synthesis of compound 45.4. To a solution of 1.1 (0.120 g, 0.278 mmol,1.0 eq) in n-butanol (5 ml) were added 45.3 (0.081 g, 0.278 mmol, 1.0eq) and DIPEA (0.107 g, 0.835 mmol, 3.0 eq). Reaction was stirred at100° C. for 2 h. After completion of the reaction, solvents were removedunder reduced pressure to obtain crude 45.4 0.120 g, 62.61%). MS (ES):m/z 689.72 [M+H]⁺.

Synthesis of compound 45.5. Compound 45.4 (0.120 g, 0.173 mmol, 1.0 eq)was dissolved in HBr/HOAc (2 mL) and stirred at room temperature for 1hour. After completion of the reaction, mixture was poured into waterand basified with satd. NaHCO₃ solution and extracted with EtOAc.Organic layers were combined, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to get pure 45.5 (0.055 g, 71.9%). MS (ES): m/z 439.42[M+H]⁺.

Synthesis of compound I-45. Compound 45.5 (0.055 g, 0.125 mmol, 1.0 eq)was dissolved in MeOH (2 mL) at 0° C. 2N NaOH solution (0.165 ml, 0.375mmol, 3.0 eq.) was added at same temperature. Reaction mixture wasstirred at room temperature for 1 h. After completion of the reaction,mixture was acidified by using solution of HCl in dioxane. The solventwas removed under reduced pressure to obtain crude which was purified bypreparative HPLC to furnish I-45 (0.025 g, 46.9%). MS (ES): m/z 425.40[M+H]⁺; NMR (400 MHz, MeOD): δ 8.18 (s, 1H), 7.89-7.86 (d, 2H),7.60-7.54 (m, 3H), 7.17-7.11 (m, 2H), 4.51 (s, 2H), 1.89 (s, H).

Example 46. Synthesis of(R)-2-amino-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)phenyl)propanoicacid hydro-chloride, I-46

Synthesis of compound 46.1. Compound 46.1 was prepared by chiralseparation of 45.2. MS (ES): m/z 294.35 [M+H]⁺, ¹H NMR (400 MHz,DMSO-d₆): δ 7.06-7.04 (d, 2H), 6.50-6.48 (d, 2H), 5.10 (s, 2H), 3.55 (s,3H), 1.67 (s, 3H), 1.36 (s, 9H).

Synthesis of compound 46.2. Compound 46.2 was prepared using equivalentprocedure as described for synthesis of compound 45.4. MS (ES): m/z689.72 [M+H]⁺.

Synthesis of compound 46.3. Compound 46.3 was prepared using the sameprocedure as described for preparation of 45.5. MS (ES): m/z 439.42[M+H]⁺.

Synthesis of compound I-46. Compound I-46 was prepared using the sameprocedure as described for preparation of compound I-45. MS (ES): m/z425.40 [M+H]⁺, ¹H NMR (400 MHz, MeOD): δ 8.30 (s, 1H), 7.88-7.86 (d,2H), 7.58-7.52 (m, 3H), 7.16-7.12 (m, 2H), 4.51 (s, 2H), 1.89 (s, 3H).

Example 47. Synthesis of4-((5-(7-oxa-4-azaspiro[2.5]octan-4-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-47

Synthesis of compound 47.1. To a solution of 20.1 (0.120 g, 0.591 mmol,1.0 eq) in 1,4-dioxane (3 ml) were added 7-oxa-4-azaspiro[2.5]octane(0.088 g, 0.591 mmol, 1.0 eq) and sodium Tert-butoxide (0.17 g, 1.77mmol, 3.0 eq). The reaction mixture was degassed for 10 min. under argonatmosphere, then Pd₂(dba)₃ (0.054 g, 0.059 mmol, 0.1 eq) and2-Dicylcohexylphosphino-2′-(N,N-dimethylamino)-biphenyl(0.046 g, 0.118mmol, 0.2 eq) were added, and again degassed for 5 minutes. The reactionwas stirred at 100° C. for 3 h. After completion of the reaction,mixture was poured into water and product was extracted with EtOAc.Organic layers were combined, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to furnish 47.1 (0.059 g, 42.43%). MS (ES): m/z 235.24[M+H]⁺.

Synthesis of compound 47.2. To a solution of 47.1 (0.059 g, 0.25 mmol,1.0 eq) in MeOH (8 mL) was added 10% Pd/C (0.06 g) under nitrogenatmosphere. It was purged with H₂ gas for 1 hour. Reaction mixture wasfiltered through celite and obtained filtrate was concentrated underreduced pressure to get crude 47.2 (0.045 g, 87.41%) which was used assuch for the next step, MS (ES): m/z 205.26 [M+H]⁺.

Synthesis of compound 47.3. To a solution of 4.4 (0.100 g, 0.232 mmol,1.0 eq) in 1,4-dioxane (3 ml) was added 47.2 (0.045 g, 0.232 mmol, 1.0eq) and K₂CO₃ (0.080 g, 0.581 mmol, 2.5 eq). The reaction mixture wasdegassed for 10 min. under argon atmosphere, then Pd₂(dba)₃ (0.021 g,0.023 mmol, 0.1 eq) and Xantphos (0.026 g, 0.046 mmol, 0.2 eq) wereadded, and again degassed for 5 min. Reaction was stirred at 100° C. for3 hours. After completion of the reaction, mixture was poured into waterand product was extracted with EtOAc. Organic layers were combined,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude which was purified by column chromatography to furnish 47.3 (0.075g, 53.89%). MS(ES): m/z 599.64 [M+H]⁺.

Synthesis of compound I-47. Compound 47.3 (0.075 g, 0.125 mmol, 1.0 eq)was dissolved in TFA (5 mL) and heated at 70° C. for 6 hours. Aftercompletion of the reaction, trifluoroacetic acid was removed underreduced pressure. Water was added to reaction mixture, basified withsatd. NaHCO₃ and extracted with EtOAc. Organic layers were combined,dried over sodium sulphate and concentrated under reduced pressure toobtain crude which was purified by column chromatography to furnish I-47(0.032 g, 56.9%). MS (ES): m/z 449.46 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz):δ 9.53 (s, 1H), 8.82 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 7.59-7.47 (m,2H), 7.28-7.24 (t, 2H), 7.10-7.08 (d, 1H), 4.41 (s, 2H), 3.63-3.53 (m,2H), 3.50-3.40 (m, 4H), 0.90-0.84 (t, 2H), 0.72 (s, 2H).

Example 48. Synthesis of2-(2,6-difluorophenyl)-4-((4-(1,3-dimethyl-2-oxoindolin-3-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one,i-298

Synthesis of compound 48.2. To a solution of compound 48.1 (5 g, 20.57mmol, 1.0 eq.) in THF (50 mL) was added Mel (3.21 g, 22.6 mmol, 1.1 eq.)and 18-crown-6 (1.35 g, 5.14 mmol, 0.25 eq.). The reaction was cooled to−78° C. Potassium tert-butoxide (2.53 g, 22.63 mmol, 1.1 eq.) was addedto the reaction mixture and it was stirred at room temperature for 4days. After completion of the reaction, mixture was poured into water,NH₄Cl solution was added and product was extracted with EtOAc. Organiclayers were combined, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude which was purified by column chromatography toget pure 48.2 (5 g, 89.09%). MS (ES): m/z 257.13 [M+H]⁺.

Synthesis of compound 48.3. To a solution of compound 48.2 (5.0 g, 19.45mmol, 1.0 eq) in EtOH (100 mL), a solution of NaOH (3.9 g, 97.2 mmol,5.0 eq.) in water (20 mL) was added. Reaction was stirred at roomtemperature for 3 hours. After completion of the reaction, solvent wasevaporated under reduced pressure and reaction mixture was poured intowater. Aqueous layer was acidified with HCl and product was extractedwith EtOAc. Organic layers were combined and dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to get pure 48.3 (3.73 g, 83.7%). MS (ES): m/z229.07 [M+H]⁺.

Synthesis of compound 48.4. To a solution of 48.3 (3.7 g, 16.3 mmol, 1.0eq) in CH₂Cl₂ (60 ml) was added 2-fluoro-N-methylaniline (2.03 g, 16.28mmol, 1.0 eq.) at room temperature. The reaction mixture was cooled to0° C. and DMAP (0.397 g, 3.25 mmol, 0.2 eq.) was added. Furtherdicyclohexyl carbodiimide (4.0 g, 19.5 mmol, 1.2 eq.) was added to thereaction mixture at 0° C. The reaction mixture was stirred at roomtemperature for 24 h. After completion of the reaction, mixture waspoured into water and extracted with CH₂Cl₂. Organic layers werecombined, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude which was purified by column chromatography to furnish pure48.4 (4 g, 73.1%). MS (ES): m/z 336.20 [M+H]⁺.

Synthesis of compound 48.5. To a solution of compound 48.4 (1 g, 2.97mmol, 1.0 eq.) in DMF (10 mL) was added potassium tert-butoxide (0.66 g,5.95 mmol, 2.0 eq.). The reaction mixture was stirred at 80° C. for 24h. After completion of the reaction, mixture was poured into water andproduct was extracted with EtOAc. Organic layers were combined, driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudewhich was purified by column chromatography to furnish 48.5 (0.28 g,29.8%). MS (ES): m/z 316.20 [M+H]⁺.

Synthesis of compound 48.6. To a solution of 48.5 (0.28 g, 0.88 mmol,1.0 eq) in 1,4-dioxane (20 mL) was added benzyl amine (0.19 g, 1.77mmol, 2.0 eq.) and Cs₂CO₃ (0.86 g, 2.65 mmol, 3.0 eq.). The reactionmixture was degassed for 30 minutes using argon, then Pd₂(dba)₃ (0.081g, 0.09 mmol, 0.1 eq) and2-Dicylcohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (0.069 g, 0.18mmol, 0.2 eq) were added, and suspension was again degassed for 5 min.Reaction was stirred at 100° C. for 3 h. After completion of thereaction, mixture was poured into water and product was extracted withEtOAc. Organic layers were combined, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude which was purified by columnchromatography to furnish 48.6 (0.15 g, 49.46%). MS (ES): m/z 342.44[M+H]⁺.

Synthesis of compound 48.7. To a suspension of Pd(OH)₂ (0.02 g) in MeOH(5 ml) was added 48.6 (0.15 g, 0.44 mmol, 1.0 eq) under nitrogen. It waspurged with H₂ gas for 1 h. Reaction mixture was filtered through celiteand obtained filtrate was concentrated under reduced pressure to getcrude 48.7 (0.1 g, 90.5%) which was used as such for the next step, MS(ES): m/z 252.32 [M+H]⁺.

Synthesis of compound 48.8. To a solution of 1.1 (0.08 g, 0.185 mmol,1.0 eq) in n-butanol (2 mL) was added 48.7 (0.046 g, 0.185 mmol, 1.0 eq)and DIPEA (0.071 g, 0.556 mmol, 3.0 eq). The reaction mixture wasstirred at 90° C. for 3 h. After completion of the reaction, mixture waspoured into water and product was extracted with EtOAc. Organic layerswere combined, dried over Na₂SO₄ and concentrated under reduced pressureto obtain crude which was purified by column chromatography to furnish48.8 (0.08 g, 66.7%). MS(ES): m/z 647.68 [M+H]⁺.

Synthesis of compound I-48. Compound 48.8 (0.08 g, 0.123 mmol, 1.0 eq)was dissolved in HBr/HOAc (1 ml). Reaction was stirred at roomtemperature for 30 minutes. After completion of the reaction, water wasadded to reaction mixture and basified with satd. NaHCO₃ and extractedwith EtOAc. Organic layers were combined, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to furnish I-48 (0.05 g, 81.4%). MS (ES): m/z497.51 [M+H]⁺; NMR (DMSO-d₆, 400 MHz): δ 9.06 (s, 1H), 8.90 (s, 1H),7.71-7.04 (m, 11H), 4.47 (s, 2H), 3.18 (s, 3H) 1.66 (s, 3H).

Example 49. Synthesis of2-(2,6-difluorophenyl)-4-((2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-49

Synthesis of compound 49.2. Compound 49.1 (19 g, 107.9 mmol, 1.0 eq.)was dissolved in CH₂Cl₂ (200 mL) and cooled at 0° C. N,N-Diisopropylamine (53.5 ml, 0.375 mmol, 3.48 eq.) was added and mixture was stirredat room temperature for 15 h. After completion of the reaction, reactionmixture was poured into water and product was extracted with CH₂Cl₂.Organic layer was combined and dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to furnish 49.2 (24 g, 92.35%). MS (ES): m/z 240.73[M+H]⁺.

Synthesis of compound 49.3. The compound 49.2 (24.0 g, 100 mmol, 1.0 eq)was dissolved in diethyl ether (200 mL) and cooled to −75° C.N,N-Diisopropyl amine (72 mL, 500 mmol, 5 eq.) and n-BuLi (200 ml, 500mmol, 5.0 eq.) were added dropwise to the reaction mixture at −78° C.Reaction was stirred for 15 minutes at −78° C., then DMF (12 ml, 150mmol, 1.5 eq.) was added at −78° C. and reaction was stirred for 1 h.After completion of the reaction, mixture was poured into water,quenched with 10% citric acid and extracted with diethyl ether. Organiclayers were combined, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude which is purified by column chromatography tofurnish 49.3 (23.3 g, 86.8%). MS (ES): m/z 268.74 [M+H]⁺.

Synthesis of compound 49.4. To a solution of 49.3 (23.25 g, 86.51 mmol,1.0 eq) in ethanol (500 ml) was added NaBH₄ (23.34 g, 614 mmol, 7.1eq.). Reaction stirred at room temperature for 2 h. After completion ofthe reaction, reaction mixture was poured into water, quenched with 1NHCl and extracted with EtOAc. Organic layers were combined, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude which waspurified by column chromatography to provide 49.4 (20 g, 85.4%). MS(ES): m/z 270.76 [M+H]⁺.

Synthesis of compound 49.5. Compound 49.4 (20 g, 74.1 mmol, 1.0 eq.) wasadded in 6N HCl solution. Reaction was heated at 120° C. for 2 h. Aftercompletion of the reaction, mixture was cooled, basified with sodiumcarbonate and the product was extracted with EtOAc. Organic layers werecombined, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude which was purified by column chromatography to furnish 49.5(5.69 g, 45.43%). MS(ES): m/z 169.56 [M+H]⁺.

Synthesis of compound 49.6. To a solution of 49.5 (5.69 g, 33.55 mmol,1.0 eq) in ethanol (100 ml) was added NaBH₄ (8.92 g, 234.9 mmol, 7.0eq.). Reaction was stirred at room temperature for 2 h. After completionof the reaction, mixture was poured into water, quenched with 1N HClsolution and extracted with EtOAc. Organic layers were combined, driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudewhich was purified by column chromatography to furnish 49.6 (2.1 g,36.05%). MS (ES): m/z 173.60 [M+H]⁺.

Synthesis of compound 49.7. To a solution of 49.6 (2.1 g, 12.1 mmol, 1.0eq) in CH₂Cl₂ (30 mL) was added SOCl₂ (7.22 g, 60.7 mmol, 5.0 eq.).Reaction was heated at 50° C. till it becomes clear. Thionyl chloridewas removed by distillation. Dry CH₂Cl₂ was added and the reactionmixture was cooled to 0° C. Isopropyl amine (3.58 g, 60.7 mmol, 5.0 eq.)was added under nitrogen atmosphere and the reaction mixture was stirredfor 1.5 h at same temperature. After completion of the reaction, mixturewas poured into water and product was extracted with CH₂Cl₂. Organiclayers were combined, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude which was purified by column chromatography tofurnish 49.7 (0.6 g, 25.22%). MS (ES): m/z 196.68 [M+H]⁺.

Synthesis of compound 49.8. Compound 49.7 (0.55 g, 28.06 mmol, 1.0 eq)was dissolved in 1,4-dioxane (20 ml) and was degassed using argon for 10minutes. 2,4-Dimethoxy benzyl amine (0.703 g, 42.09 mmol, 1.5 eq.) andcesium carbonate (1.828 g, 5.612 mmol, 2.0 eq.) were added to thereaction mixture. The reaction mixture was degassed for further 10minutes. Dicylcohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (0.220 g,0.561 mmol, 0.5 eq.) and Pd₂(dba)₃ (0.256 g, 0.280 mmol, 0.1 eq) wereadded to the reaction mixture and it was heated at 110° C. for 24 h.After completion of the reaction, mixture was poured into water andproduct was extracted with CH₂Cl₂. Organic layers were combined, driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudewhich was purified by column chromatography to get pure 49.8 (0.35 g,71.0%). MS (ES): m/z 176.24 [M+H]⁺.

Synthesis of compound 49.9. Compound 49.8 (0.25 g, 0.764 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (5 mL). Triethyl silane (0.27 g, 2.29 mmol, 3.0eq.) and TFA (3 mL) were added to the reaction mixture. The reactionmixture was stirred at room temperature for 24 h. After completion ofreaction, mixture was concentrated under reduced pressure, basified byNaHCO₃ solution and extracted with EtOAc. Organic layers were combined,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude which was purified by column to yield 49.9 (0.075 g, 29.8%). MS(ES): m/z 11125 [M+H]⁺.

Synthesis of compound 49.10. To a solution of 4.4 (0.150 g, 0.348 mmol,1.0 eq) in 1,4-dioxane (3 ml) was added 49.9 (0.067 g, 0.383 mmol, 1.1eq) and K₂CO₃ (0.120 g, 0.871 mmol, 2.5 eq). The reaction mixture wasdegassed for 10 min. using argon, then Pd₂(dba)₃ (0.031 g, 0.034 mmol,0.1 eq) and Xantphos (0.040 g, 0.069 mmol, 0.2 eq) were added, andsuspension was again degassed for 5 min. The reaction was stirred at100° C. for 1.5 h. After completion of the reaction, mixture was pouredinto water and product was extracted with EtOAc. Organic layers werecombined, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude which was purified by column chromatography to furnish49.10 (0.035 g, 17.6%). MS(ES): m/z 571.63 [M+H]⁺.

Synthesis of compound I-49. Compound 49.10 (0.030 g, 0.052 mmol, 1.0 eq)was dissolved in HBr/HOAc (0.5 ml) and the reaction was stirred at roomtemperature for 1 h. After completion of the reaction, water was added.Mixture was basified with saturated bicarbonate solution and product wasextracted with EtOAc. Organic layers were combined and dried over Na₂SO₄and concentrated under reduced pressure to obtain dehydrated crude whichwas purified by column chromatography to furnish I-49 (0.002 g, 9.0%).MS (ES): m/z 421.45 [M+H]⁺; ¹H NMR (CD₃OD, 400 MHz): δ 8.70 (s, 1H),8.24 (s, 1H), 7.56-7.52 (m, 1H), 7.17-7.13 (t, 2H), 7.05 (s, 1H), 4.48(s, 2H), 4.04-4.01 (s, 4H), 2.88-2.85 (m, 1H), 1.25-1.23 (d, 3H).

Example 50. Synthesis of4-((4-(4-oxa-7-azaspiro[2.5]octane-7-carbonyl)phenyl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-50

Synthesis of compound 50.1. To a solution of p-aminobenzoic acid (0.080g, 0.583 mmol, 1.0 eq) in DMF (2 mL) was added HATU (0.33 g, 0.88 mmol,1.5 eq) at 0° C. The reaction was stirred at 0° C. for 45 minutes. Thereaction was warmed to ambient temperature and stirred for additionalten minutes. Further 4-oxa-7-azaspiro[2.5]octane (0.104 g, 0.700 mmol,1.2 eq) and DIPEA (0.150 g, 1.17 mmol, 2.0 eq) were added at 0° C. andthe reaction was allowed to stir at room temperature for 2 hours. Aftercompletion of the reaction, mixture was poured into water and productwas extracted with EtOAc. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. Crude was purified by column chromatography tofurnish 50.1 (0.070 g, 51.66%). MS (ES): m/z 232.28 [M+H]⁺.

Synthesis of compound 50.2. To a solution of 4.4 (0.100 g, 0.232 mmol,1.0 eq) in 1,4-dioxane (3 mL) was added 50.1 (0.054 g, 0.23 mmol, 1.0eq) and K₂CO₃ (0.064 g, 0.47 mmol, 2.0 eq). Reaction mixture wasdegassed for 10 minutes under argon atmosphere, then Pd₂(dba)₃ (0.021 g,0.023 mmol, 0.1 eq) and Xantphos (0.026 g, 0.046 mmol, 0.2 eq) wereadded, and again degassed for 5 minutes. Reaction was stirred at 100° C.for 2 h. After completion of the reaction, reaction mixture was pouredin water and product was extracted with EtOAc. Organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to furnish 50.2 (0.098, 67.4%). MS(ES): m/z 626.66[M+H]⁺.

Synthesis of compound I-50. The compound 50.2 (0.098 g, 0.156 mmol, 1.0eq) was dissolved in HBr/HOAc (33% solution, 3 mL) and stirred at roomtemperature for 1 hour. After completion of the reaction, mixture waspoured into ice-water and basified with satd. NaHCO₃ and with EtOAc.Organic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to furnish I-50 (0.041 g, 55.0%). MS(ES): m/z476.48 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): 9.17 (s, 1H), 8.77 (s, 1H),7.56-7.50 (m, 1H), 7.43 (s, 4H), 7.24-7.20 (m, 3H), 4.40 (s, 2H),3.64-3.43 (m, 6H), 0.85-0.52 (m, 4H).

Example 51. Synthesis of4-((4-(7-oxa-4-azaspiro[2.5]octane-4-carbonyl)phenyl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-51

Synthesis of compound 51.1. To a solution of 7-oxa-4-azaspiro[2.5]octane(0.080 g, 0.540 mmol, 1.0 eq) in dry THF were added K₂CO₃ (0.149 g,1.081 mmol, 2.0 eq) and p-nitrobenzoyl chloride (0.1 g, 0.54 mmol, 1.0eq) at 0° C. The reaction mixture was stirred at room temperature for 2h. After completion of the reaction, mixture was poured into crushedice, neutralized by satd. NaHCO₃ and extracted with EtOAc. Organiclayers were combined, washed with brine, dried over sodium sulphate andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to furnish 51.1 (0.12 g, 84.9%). MS(ES): m/z262.27 [M+H]⁺.

Synthesis of compound 51.2. To a suspension of Pd/C (0.025 g) inmethanol (3 mL) was added 51.1 (0.12 g, 0.46 mmol, 1.0 eq) in MeOH (2mL). Suspension was purged with H₂ gas for 1.5 hr. After completion ofthe reaction, mixture was filtered through celite, washed with methanoland the filtrate was concentrated under reduced pressure to obtain crudematerial. The crude was purified by column chromatography to get pure51.2 (0.06 g, 56.5%). MS(ES): m/z 232.28 [M+H]⁺.

Synthesis of compound 51.3. To a mixture of 4.4 (0.10 g, 0.23 mmol, 1.0eq) in 1,4-dioxane (3 mL) was added 51.2 (0.053 g, 0.232 mmol, 1.0 eq)and K₂CO₃ (0.064 g, 0.47 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 minutes under argon atmosphere, then Pd₂(dba)₃ (0.021 g,0.023 mmol, 0.1 eq) and Xantphos (0.026 g, 0.046 mmol, 0.2 eq) wereadded, again degassed for 5 min. The reaction was stirred at 100° C. for12 h. After completion of the reaction, mixture was poured into waterand product was extracted with EtOAC. Organic layers were combined,washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude which was purified by column chromatography tofurnish 51.3 (0.093 g, 63.94%). MS(ES): m/z 626.66 [M+H]⁺.

Synthesis of compound I-51. Compound 51.3 (0.093 g, 0.148 mmol, 1.0 eq)was dissolved in HBr/HOAc (2 mL) and reaction was stirred at roomtemperature for 1 h. After completion of reaction, reaction mixture waspoured in water, basified with satd. NaHCO₃ and extracted with EtOAc.Organic layers were combined, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to furnish I-51 (0.041 g, 57.9%). MS(ES): m/z 476.48[M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): 9.17 (s, 1H), 8.78 (s, 1H), 7.56-7.39(m, 5H), 7.24-7.20 (m, 3H), 4.41 (s, 2H), 3.63 (s, 4H), 3.54 (s, 2H),0.78 (s, 4H).

Example 52. Synthesis of4-((5-(2-oxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-52

Synthesis of 52.3. To a mixture of 52.1 (0.045 g, 0.118 mmol, 1.0 eq) in1,4-dioxane (1.0 mL) was added 52.2 (0.023 g, 0.118 mmol, 1.0 eq) andK₂CO₃ (0.048 g, 0.354 mmol, 3.0 eq). The reaction mixture was degassedfor 10 minutes using argon, then Pd₂(dba)₃ (0.010 g, 0.011 mmol, 0.1 eq)and Xantphos (0.013 g, 0.023 mmol, 0.2 eq) were added and mixture wasdegassed for additional five minutes. The reaction was stirred at 100°C. for 1 hour. After completion of the reaction, mixture was poured intowater and product was extracted with EtOAc. Organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude material. The crude was purified bycolumn chromatography to furnish 52.3 (0.045 g, 61.8%). MS(ES): m/z577.63 [M+H]⁺.

Synthesis of I-52. Compound 52.3 (0.045 g, 0.077 mmol, 1.0 eq) wasdissolved in CH₂Cl₂ (1 mL) and TFA (0.5 mL) was added to the reaction.The reaction was stirred at room temperature for 1 hour. Aftercompletion of the reaction, mixture was poured into water, basified withNaHCO₃ solution and extracted with CH₂Cl₂. Organic layers were combinedand dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude which was purified by column chromatography to furnish I-52 (0.025g, 59.9%). MS(ES): m/z 477.52 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.50(s, 1H), 8.80 (s, 1H), 8.36 (s, 1H), 8.03 (d, 1H), 7.60-7.53 (m, 1H),7.47-7.44 (dd, 1H), 7.27-7.23 (t, 2H), 7.09-7.07 (d, 1H), 4.40 (s, 2H),3.76-3.73 (t, 2H), 3.46 (s, 2H), 3.19-3.07 (m, 4H), 1.74-1.70 (t, 2H),1.61-1.53 (m, 4H).

Example 53. Synthesis of4-((5-(l-oxa-9-azaspiro[5.5]undecan-9-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-53

Synthesis of compound 53.2. To a solution of 53.1 (0.17 g, 1.19 mmol,1.0 eq) in DMSO (3 mL) was added 1-oxa-9-azaspiro[5.5]undecane (0.229 g,0.119 mmol, 1.0 eq.) and DIPEA (1.54 g, 11.9 mmol, 10.0 eq.). Thereaction was stirred at 110° C. for 2 hours. After completion of thereaction, mixture was poured into water and extracted with EtOAc.Organic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. This waspurified by tituration with hexane to provide 53.2 (0.2 g, 60.3%).MS(ES): m/z 277.32 [M+H]⁺.

Synthesis of compound 53.3. To a suspension of 10% Pd/C (0.05 g) in MeOH(2 mL) was added a solution of 53.2 (0.2 g, 0.72 mmol, 1.0 eq) in MeOH(3.0 mL) under nitrogen atmosphere. Reaction mixture was purged with H₂gas for 2 hours. After completion of the reaction, mixture was filteredthrough celite, washed with MeOH and concentrated under reducedpressure. The crude material was purified by column chromatography tofurnish 53.3 (0.14 g, 78.5%) MS (ES): m/z 247.34 [M+H]⁺.

Synthesis of compound 53.4. To a mixture of 4.4 (0.1 g, 0.23 mmol, 1.0eq) in 1,4-dioxane (3 mL) was added 53.3 (0.063 g, 0.255 mmol, 1.1 eq)and K₂CO₃ (0.064 g, 0.465 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 minutes using argon gas, then Pd₂(dba)₃ (0.021 g, 0.023mmol, 0.1 eq) and Xantphos (0.026 g, 0.046 mmol, 0.2 eq) were added andsuspension was degassed for additional 5 minutes. The reaction wasstirred at 110° C. for 1 hour. After completion of the reaction, mixturewas poured into water and extracted with EtOAc. Organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude material. The crude was purified bycolumn chromatography to provide 53.4 (0.09 g, 60.4%). MS(ES): m/z641.72 [M+H]⁺.

Synthesis of compound I-53. Compound 53.4 (0.09 g, 0.14 mmol, 1.0 eq)was dissolved in HBr/HOAc (3 mL) and reaction was stirred at roomtemperature for 1 hour. After completion of the reaction, mixture waspoured into water, basified with NaHCO₃ solution and extracted withEtOAc. Organic layers were combined, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude. The crude was purified by columnchromatography to provide I-53 (0.038 g, 55.1%). MS(ES): m/z 491.54[M+H]⁺; NMR (DMSO-d₆, 400 MHz): δ 9.49 (s, 1H), 8.79 (s, 1H), 8.35 (s,1H), 8.02 (d, 2H), 7.59-7.54 (m, 1H), 7.46-7.43 (dd, 1H), 7.27-7.23 (t,2H), 7.08-7.06 (d, 1H), 4.40 (s, 2H), 3.58-3.55 (t, 2H), 3.33-3.28 (t,2H), 2.98-2.93 (t, 2H), 1.89-1.86 (d, 2H), 1.59-1.39 (m, 8H).

Example 54. Synthesis of4-((4-(1-oxa-9-azaspiro[5.5]undecane-9-carbonyl)phenyl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-54

Synthesis of compound 54.2. To a solution of 54.1 (0.2 g, 1.08 mmol, 1.0eq) in CH₂Cl₂ (2 mL) was added 1-oxa-9-azaspiro[5.5]undecane (0.21 g,1.08 mmol, 1.0 eq) and DIPEA (0.33 g, 3.24 mmol, 3.0 eq). The reactionwas stirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into water and extracted with EtOAc.Organic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain pure 54.2 (0.16 g, 48.8%).MS(ES): m/z 304.35 [M+H]⁺.

Synthesis of compound 54.3. To a suspension of 10% Pd/C (0.05 g) in MeOH(2 mL) was added a solution of 54.2 (0.16 g, 0.53 mmol, 1.0 eq) in MeOH(3 mL) under nitrogen. Reaction mixture was purged with H₂ gas for 1hour. After completion of the reaction, mixture was filtered throughcelite and washed with MeOH. Obtained filtrate was concentrated underreduced pressure to furnish 54.3 (0.05 g, 34.7%) MS (ES): m/z 274.36[M+H]⁺.

Synthesis of compound 54.4. To a mixture of 4.4 (0.075 g, 0.174 mmol,1.0 eq) in 1,4-dioxane (3 mL) was added 54.3 (0.047 g, 0.174 mmol, 1.0eq) and K₂CO₃ (0.048 g, 0.348 mmol, 2.0 eq). Reaction mixture wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.015 g, 0.017mmol, 0.1 eq) and Xantphos (0.02 g, 0.034 mmol, 0.2 eq) were added.Suspension was degassed for additional 5 minutes. The reaction wasstirred at 110° C. for 2 hours. After completion of the reaction,mixture was poured into water and extracted with EtOAc. Organic layerswere combined, washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude material. This crude was purifiedby column chromatography to provide 54.4 (0.07 g, 60.1%). MS(ES): m/z668.74 [M+H]⁺.

Synthesis of compound I-54. Compound 54.4 (0.07 g, 0.104 mmol, 1.0 eq)was dissolved in HBr/HOAc (3 mL, 33% HBr in AcOH) and reaction wasstirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into water, basified with satd. NaHCO₃solution and product was extracted with EtOAc. Organic layers werecombined, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material which was purified by column chromatography tofurnish I-54 (0.029 g, 53.4%). MS(ES): m/z 518.56 [M+H]⁺; ¹H NMR(DMSO-d₆, 400 MHz): δ 9.15 (s, 1H), 8.77 (s, 1H), 7.57-7.50 (m, 1H),7.41 (s, 4H), 7.23-7.18 (m, 3H), 4.41 (s, 2H), 4.09 (m, 2H), 3.56 (m,2H), 3.16 (m, 2H), 1.84-1.82 (m, 4H), 1.56 (m, 2H), 1.43-1.40 (m, 6H).

Example 55. Synthesis of2-(2,6-difluorophenyl)-4-((5-(1-(3,6-dihydro-2H-pyran-4-yl)-3,5,5-trimethyl-2-oxopyrrolidin-3-yl)pyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-55

Synthesis of compound 55.2. Acetyl chloride (15.1 g, 192.3 mmol, 3.3 eq)was added slowly to MeOH (100 mL) at room temperature. The reactionstirred at room temperature for 15 minutes. Compound 55.1 (10 g, 58.3mmol, 1.0 eq) was added slowly and the reaction mixture was allowed tostir at room temperature for 16 hours. After completion of the reaction,solvent was evaporated under reduced pressure. Satd. NaHCO₃ solution wasadded to reaction mixture and product was extracted with EtOAc. Organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain pure 55.2 (10.0 g, 92.4%).MS(ES): m/z 185.61 [M+H]⁺.

Synthesis of compound 55.3. To a solution of 55.2 (10.0 g, 54.0 mmol,1.0 eq) in toluene (100 mL) was added K₂CO₃ (16.5 g, 118.8 mmol, 2.2eq), paraformaldehyde (2.66 g, 70.19 mmol, 1.3 eq) and tetrabutylammonium chloride (1.5 g, 5.4 mmol, 0.1 eq) at room temperature. Thereaction was allowed to stir at room temperature for 2 hours. Aftercompletion of the reaction, reaction mixture was poured into water andextracted with EtOAc. Organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to obtain pure1.2 (2.6 g, 24.42%). MS(ES): m/z 197.62 [M+H]⁺.

Synthesis of compound 55.4. To a solution of 55.3 (2.6 g, 13.2 mmol, 1.0eq) in CH₃CN (40 mL) was added 2-nitro propane (1.41 g, 15.8 mmol, 1.2eq) and DBU (2.40 g, 15.82 mmol, 1.2 eq) at room temperature. Thereaction was stirred at room temperature for 6 hours. After completionof the reaction, CH₃CN was evaporated under reduced pressure, water wasadded to the reaction mixture and product was extracted with EtOAc.Organic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by column chromatography to provide 55.3 (2.2 g, 58.3%).MS(ES): m/z 286.71 [M+H]⁺.

Synthesis of compound 55.5. To a solution of NaH (0.40 g, 16.9 mmol, 2.2eq) in DMF (20 mL) at 0° C. was added 55.4 (2.2 g, 7.68 mmol, 1.0 eq)and the reaction was stirred at 0° C. for 5 minutes. Methyl iodide (2.73g, 19.2 mmol, 2.5 eq) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 1 hour.After completion of the reaction, water was added to the reactionmixture and product was extracted with EtOAc. Organic layers werecombined, washed with brine solution, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude which was purified by columnchromatography to provide pure 55.5 (1.5 g, 65.0%). MS(ES): m/z 300.74[M+H]⁺.

Synthesis of compound 55.6. To a solution of 55.5 (1.5 g, 5.0 mmol, 1.0eq) in EtOH (15.0 mL) was added iron powder (2.8 g, 50.0 mmol, 10.0 eq)and NH₄Cl (2.65 g, 50.0 mmol, 10.0 eq). The reaction mixture was stirredat 80° C. for 2 hours. After completion of the reaction, water was addedto the reaction mixture and product was extracted with EtOAc. Organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain pure product.Dichloromethane was added to the pure product and the reaction wasstirred at room temperature overnight to get pure cyclized product 55.6(0.8 g, 67.2%). MS(ES): m/z 238.72 [M+H]⁺.

Synthesis of compound 55.7. To a solution of 55.7 (0.8 g, 3.36 mmol, 1.0eq) in 1,4-dioxane (5.0 mL) was added Cs₂CO₃ (3.27 g, 10.1 mmol, 3.0 eq)and CuI (0.063 g, 0.336 mmol, 0.1 eq). The reaction mixture was degassedusing argon for 15 minutes at room temperature.4-Bromo-3,6-dihydro-2H-pyran (1.64 g, 10.1 mmol, 3.0 eq) andN,N-dimethyl ethylene diamine (0.029 g, 0.34 mmol, 0.1 eq) were added tothe reaction mixture. The reaction was stirred at 160° C. for 1 hour ina microwave reactor. After completion of the reaction, water was addedto the reaction mixture and product was extracted with EtOAc. Organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to provide 55.7 (0.3 g, 27.9%). MS(ES): m/z320.82 [M+H]⁺.

Synthesis of compound 55.8. To a solution of 55.7 (0.16 g, 0.5 mmol, 1.0eq) in 1,4-dioxane (5 mL) was added 2,4-dimethoxy benzyl amine (0.11 g,0.65 mmol, 1.3 eq) and Cs₂CO₃ (0.325 g, 10.0 mmol, 2.0 eq). The reactionmixture was degassed using argon for 30 minutes at room temperature.Devphos ligand (0.039 g, 0.1 mmol, 0.2 eq) and Pd₂(dba)₃ (0.045 g, 0.05mmol, 0.1 eq) were added to the reaction mixture. The reaction wasstirred at 100° C. for 3 hours. After completion of the reaction, waterwas added to the mixture and product was extracted with EtOAc. Organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by column chromatography to furnish 55.8 (0.09 g, 40.1%).MS(ES): m/z 451.57 [M+H]⁺.

Synthesis of compound 55.9. To a solution of 55.8 (0.06 g, 0.132 mmol,1.0 eq) in CH₂Cl₂ (2 mL) was added TFA (0.1 mL) and triethyl silane (0.1mL) at 0° C. under nitrogen atmosphere. The reaction was allowed to stirat room temperature for 2 hours. After completion of the reaction,solvent was removed under reduced pressure to furnish 55.9 (0.05 g,99.0%) MS (ES): m/z 301.39 [M+H]⁺.

Synthesis of compound 55.91. To a mixture of 52.1 (0.02 g, 0.052 mmol,1.0 eq) in 1,4-dioxane (2 mL) was added 55.9 (0.015 g, 0.52 mmol, 1.0eq) and K₂CO₃ (0.021 g, 0.157 mmol, 3.0 eq). The reaction mixture wasdegassed for 10 minutes using argon then Pd₂(dba)₃ (0.004 g, 0.005 mmol,0.1 eq) and Xantphos (0.006 g, 0.01 mmol, 0.2 eq) were added. Suspensionwas degassed for additional 5 minutes. The reaction was stirred at 100°C. for 2 hours. After completion of the reaction, mixture was pouredinto water and product was extracted with EtOAc. Organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to provide pure 55.91 (0.015 g, 40.9%). MS(ES): m/z583.40 [M+H]⁺.

Synthesis of compound I-55. Compound 55.91 (0.015 g, 0.025 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (1 mL) and TFA (0.1 mL) was added to thereaction mixture. The reaction was stirred at room temperature for 30minutes. After completion of the reaction, reaction mixture was pouredinto water, basified with satd. NaHCO₃ and extracted with EtOAc. Organiclayers were combined, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude which was purified by column chromatography toprovide I-55 (0.009 g, 64.2%). MS(ES): m/z 545.59 [M+H]⁺; ¹H NMR(DMSO-d₆, 400 MHz): δ 9.74 (s, 1H), 8.90 (s, 1H), 8.58 (s, 1H),8.37-8.36 (d, 1H), 7.81-7.78 (dd, 1H), 7.62-7.54 (m, 1H), 7.28-7.24 (t,2H), 7.17-7.14 (d, 1H), 5.70 (s, 1H), 4.43 (s, 2H), 4.17-4.16 (d, 2H),3.76-3.73 (t, 2H), 2.19-2.13 (s, 2H), 1.67 (s, 1H), 1.45 (s, 3H), 1.28(s, 3H), 1.03 (s, 3H).

Example 56. Synthesis of2-(6-fluoro-2-oxopyridin-1(2H)-yl)-4-((5-morpholinopyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-56

Synthesis of compound 56.2. Sodium metal (2.0 g) was dissolved int-butanol (50 mL) and refluxed for 1 hour. The reaction mixture wascooled to room temperature and 56.1 (5.0 g, 43.85 mmol, 1.0 eq) wasadded. The reaction was stirred at reflux temperature for 12 hours.After completion of the reaction, solvent was removed under reducedpressure. Ice cold water was added and the pH was adjusted to 3.0 byaddition of dilute HCl. The product was extracted with EtOAc. Organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to provide 56.2 (2.0 g, 40.1%). MS(ES): m/z113.09 [M+H]⁺.

Synthesis of compound 56.4. To a solution of 56.3 (1.0 g, 4.55 mmol, 1.0eq) in 1,4-dioxane (10 mL) was added 56.2 (0.51 g, 4.55 mmol, 1.0 eq)and Cs₂CO₃ (4.43 g, 13.63 mmol, 3.0 eq). The Reaction mixture wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.415 g, 0.454mmol, 0.1 eq) and Xantphos (0.525 g, 0.91 mmol, 0.2 eq) were added.Suspension was degassed for additional 5 minutes. The reaction wasstirred at 100° C. for 1 hour. After completion of the reaction,reaction mixture was poured into water and product was extracted withEtOAc. Organic layers were combined, washed with brine solution, driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudewhich was purified by column chromatography to furnish 56.4 (0.40 g,29.7%). MS(ES): m/z 296.68 [M+H]⁺.

Synthesis of compound 56.5. To a solution of 56.4 (0.3 g, 1.013 mmol,1.0 eq) in ethylene dichloride (10 mL) was added N-bromo succinimide(0.902 g, 5.067 mmol, 5.0 eq) and benzyl peroxide (0.061 g, 0.255 mmol,0.25 eq). The reaction was stirred at 100° C. for 5 hours. Aftercompletion of the reaction, mixture was poured into water and productwas extracted with EtOAc. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude which was purified by column chromatography to provide 56.5(0.175 g, 46.1%). MS(ES): m/z 375.58 [M+H]⁺.

Synthesis of compound 56.6. To a solution of 56.5 (0.175 g, 0.466 mmol,1.0 eq) in CH₂Cl₂ (3 mL) was added 2,4-dimethoxy benzyl amine (0.077 g,0.466 mmol, 1.0 eq) and Et₃N (0.094, 0.933 mmol, 2.0 eq). The reactionwas stirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into water and product was extracted withCH₂Cl₂. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.The crude was purified by column chromatography to furnish 56.6 (0.09 g,44.9%). MS(ES): m/z 429.83 [M+H]⁺.

Synthesis of compound 56.8. To a mixture of 56.6 (0.090 g, 0.209 mmol,1.0 eq) in 1,4-dioxane (2 mL) was added 56.7 (0.037 g, 0.209 mmol, 1.0eq) and K₂CO₃ (0.086 g, 0.627 mmol, 3.0 eq). The reaction mixture wasdegassed for 10 minutes using argon, then Pd₂(dba)₄ (0.018 g, 0.020mmol, 0.1 eq) and xantphos (0.023 g, 0.041 mmol, 0.2 eq) were added.Suspension was degassed for additional five minutes. The reaction wasstirred at 110° C. for 2 hours. After completion of the reaction,mixture was poured into water and product was extracted with EtOAc.Organic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by column chromatography to furnish 56.8 (0.08 g, 66.7%).MS(ES): m/z 572.60 [M+H]⁺.

Synthesis of compound I-56. Compound 56.8 (0.08 g, 0.139 mmol, 1.0 eq)was dissolved in TFA (2.0 mL). The reaction was stirred at 70° C. for 2hours. After completion of the reaction, mixture was poured into water,basified with satd. NaHCO₃ and extracted with EtOAc. Organic layers werecombined and dried over Na₂SO₄ and concentrated under reduced pressureto obtain crude material. The crude was purified by columnchromatography to provide I-56 (0.040 g, 77.5%). MS (ES): m/z 422.42[M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.51 (s, 1H), 8.68 (s, 1H),8.13-7.97 (m, 3H), 7.49-7.46 (dd, 1H), 7.14-7.03 (m, 3H), 4.25 (s, 2H),3.76-3.73 (t, 4H), 3.12-3.10 (t, 4H).

Example 57. Synthesis of4-((4-(6-azaspiro[2.5]octane-6-carbonyl)phenyl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-57

Synthesis of compound 57.1. To a solution of 6-azaspiro[2.5]octane(0.119 g, 0.808 mmol, 1.0 eq) in THF (3.0 mL) was added 54.1 (0.15 g,0.81 mmol, 1.0 eq) and Et₃N (0.245 g, 2.425 mmol, 3.0 eq) dropwise at 0°C. The reaction was stirred at room temperature for 2 hours. Aftercompletion of the reaction, water was added to the mixture and productwas extracted with EtOAc. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by titration with hexanesto provide pure 57.1 (0.16 g, 76.0%). MS(ES): m/z 260.29 [M+H]⁺.

Synthesis of compound 57.2. To a suspension of 10% Pd/C (0.050 g) inMeOH (5 mL) was added a solution of 57.1 (0.16 g, 0.614 mmol, 1.0 eq) inMeOH (1 mL) under nitrogen. Reaction mixture was purged with hydrogengas for 2 hours. After completion of the reaction, mixture was filteredthrough celite, washed with MeOH. Obtained filtrate was concentratedunder reduced pressure to get pure 57.2 (0.1 g, 70.6%) MS (ES): m/z230.31 [M+H]⁺.

Synthesis of compound 57.3. To a mixture of 4.4 (0.1 g, 0.23 mmol, 1.0eq) in 1,4-dioxane (2.0 mL) was added 57.2 (0.058 g, 0.254 mmol, 1.1 eq)and K₂CO₃ (0.063 g, 0.462 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.021 g, 0.023mmol, 0.1 eq) and Xantphos (0.026 g, 0.046 mmol, 0.2 eq) were added.Suspension was degassed for additional 5 minutes. The reaction wasstirred at 100° C. for 2 hours. After completion of the reaction,mixture was poured into water and product was extracted with EtOAc.Organic layer was combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by column chromatography to furnish 57.3 (0.088 g, 60.7%).MS(ES): m/z 624.69 [M+H]⁺.

Synthesis of compound I-57. The compound 57.3 (0.088 g, 0.14 mmol, 1.0eq) was dissolved in TFA (2.0 mL). The reaction mixture was stirred at70° C. for 1 hour. After completion of the reaction, mixture was pouredinto water, basified with satd. NaHCO₃ solution and extracted withEtOAc. Organic layers were combined, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude material. The crude was purifiedby column chromatography to furnish I-57 (0.035 g, 52.4%). MS(ES): m/z474.51 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.16 (s, 1H), 8.76 (s, 1H),7.57-7.50 (m, 1H), 7.45-7.39 (m, 4H), 7.24-7.19 (m, 3H), 4.41 (s, 2H),3.67-3.31 (m, 4H), 1.34-1.17 (m, 4H), 0.34 (m, 4H).

Example 58. Synthesis of4-((4-(3-oxa-9-azaspiro[5.5]undecane-9-carbonyl)phenyl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-58

Synthesis of compound 58.1. To a mixture of 52.1 (0.06 g, 0.157 mmol,1.0 eq) in 1,4-dioxane (2.0 mL) was added(4-aminophenyl)(3-oxa-9-azaspiro[5.5]undecan-9-yl)methanone (0.043 g,0.157 mmol, 1.0 eq) and K₂CO₃ (0.065 g, 0.473 mmol, 3.0 eq). Suspensionwas degassed for 10 minutes using argon, then Pd₂(dba)₃ (0.014 g, 0.015mmol, 0.1 eq) and Xantphos (0.018 g, 0.031 mmol, 0.2 eq) were added. Thereaction was stirred at 100° C. for 2 hours. After completion of thereaction, mixture was poured into water and extracted with EtOAc.Organic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by column chromatography to furnish 58.1 (0.055 g, 56.4%).MS(ES): m/z 618.68 [M+H]⁺.

Synthesis of compound I-58. Compound 58.1 (0.055 g, 0.088 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (1.0 mL) and TFA (0.5 mL) was added to thereaction. The reaction was stirred at room temperature for 1 hour. Aftercompletion of the reaction, mixture was poured into water, basified withNaHCO₃ solution and extracted with CH₂Cl₂. Organic layers were combined,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude which was purified by column chromatography to furnish I-58 (0.042g, 91.1%). MS(ES): m/z 518.56 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): 9.21(s, 1H), 8.78 (s, 1H), 7.57-7.53 (m, 1H), 7.42 (s, 4H), 7.24-7.19 (m,3H), 4.42 (s, 2H), 3.55-3.46 (m, 8H), 1.46 (m, 8H).

Example 59. Synthesis of2-(2,6-difluorophenyl)-4-((5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-59

Synthesis of compound 59.1. To a solution of 53.1 (0.2 g, 1.40 mmol, 1.0eq) in DMSO (2.0 mL) was added (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrolehydrochloride (0.21 g, 1.40 mmol, 1.0 eq.) and DIPEA (2.45 mL, 14.07mmol, 10.0 eq.). The reaction mixture was stirred at 120° C. for 1 hour.After completion of the reaction, mixture was poured into water andproduct was extracted with EtOAc. Organic layers were combined, washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude which was purified by column chromatography to provide 59.1(0.23 g, 69.5%). MS(ES): m/z 236.17 [M+H]⁺.

Synthesis of compound 59.2. To a suspension of 10% Pd/C (0.025 g) inMeOH (5.0 mL) was added a solution of 59.1 (0.225 g, 0.957 mmol, 1.0 eq)in MeOH (5.0 mL) under nitrogen atmosphere. Suspension was purged for 2hours with H₂ gas. After completion of the reaction, mixture wasfiltered through celite, washed with MeOH and obtained filtrate wasconcentrated under reduced pressure to obtain crude 59.2 (0.18 g) MS(ES): m/z 206.26 [M+H]⁺

Synthesis of compound 59.3. To a solution of 52.1 (0.065 g, 0.17 mmol,1.0 eq) in 1,4-dioxane (2.0 mL) was added 59.2 (0.038 g, 0.187 mmol, 1.1eq) and K₂CO₃ (0.058 g, 0.426 mmol, 2.5 eq). The reaction mixture wasdegassed for 10 minutes under argon atmosphere, then Pd₂(dba)₃ (0.015 g,0.017 mmol, 0.1 eq) and xantphos (0.019 g, 0.034 mmol, 0.2 eq) wereadded, and suspension was degassed for additional 5 min. The reactionwas stirred at 100° C. for 2 hours. After completion of the reaction,mixture was poured into water and product was extracted with EtOAc.Organic layers were combined, washed with brine solution, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.The crude was purified by column chromatography to provide 59.3 (0.065g, 69.7%). MS(ES): m/z 551.5 [M+H]⁺.

Synthesis of compound I-59. Compound 59.3 (0.065 g, 0.118 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (1.5 mL) and TFA (0.3 mL) was added to thereaction mixture. The reaction was stirred at room temperature for 1hour After completion of reaction, mixture was poured into water,basified with NaHCO₃ solution and extracted with EtOAc. Organic layerswere combined, dried over Na₂SO₄ and concentrated under reduced pressureto obtain crude which was purified by trituration with Et₂O get pureI-59 (0.030 g, 84.7%). MS(ES): m/z 450.37 [M+H]⁺; ¹H NMR (DMSO-d₆, 400MHz): δ 9.48 (s, 1H), 8.81 (s, 1H), 8.28 (s 1H), 7.79-7.78 (d, 1H),7.54-7.61 (m, 1H), 7.28-7.24 (t, 2H), 7.18-7.15 (m, 1H), 7.11-7.09 (d,1H), 4.41 (s, 2H), 3.86-3.83 (t, 2H), 3.52-3.50 (t, 2H), 3.32-3.28 (t,2H), 3.19-3.17 (d, 2H), 2.98 (bs, 2H).

Example 60. Synthesis of4-(4-((5-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3,5-difluorobenzonitrile,I-60

Synthesis of compound 60.2. To a solution of 60.1 (0.070 g, 0.155 mmol,1.0 eq) in 1,4-dioxane (2.0 mL) was added 20.3 (0.032 g, 0.155 mmol, 1.0eq) and K₂CO₃ (0.043 g, 0.31 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 minutes under argon atmosphere, then Pd₂(dba)₃ (0.014 g,0.0155 mmol, 0.1 eq) and Xantphos (0.018 g, 0.031 mmol, 0.2 eq) wereadded. Suspension was degassed again for 5 minutes. The reaction wasstirred at 110° C. for 1 hour. After completion of the reaction, mixturewas poured into water and product was extracted with EtOAc. Organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by column chromatography to provide 60.2 (0.070 g, 70.9%).MS(ES): m/z 572.62 [M+H]⁺.

Synthesis of compound I-60. Compound 60.2 (0.070 g, 0.122 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (3.0 mL) and TFA (0.4 mL) was added to thereaction mixture. The reaction mixture was stirred at room temperaturefor 1 hour. After completion of the reaction, mixture was poured intowater, basified with satd. NaHCO₃ solution and extracted with EtOAc.Organic layers were combined, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude which was purified by trituration withn-pentane and diethyl ether to provide pure I-60 (0.047 g, 81.4%).MS(ES): m/z 472.50 [M+H]⁺; NMR (DMSO-d₆, 400 MHz): δ 9.55 (s, 1H), 8.85(s, 1H), 8.39 (s, 1H), 8.03 (d, 1H), 7.99-7.97 (d, 2H), 7.49-7.46 (dd,1H), 7.11-7.09 (d, 1H), 4.41 (s, 2H), 3.20-3.17 (t, 4H), 1.46-1.40 (t,4H), 0.329 (s, 4H).

Example 61. Synthesis of2-(2,6-difluorophenyl)-4-((1-hydroxy-1,3-dihydro-benzo-[c][1,2]oxaborol-5-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-61

Synthesis of compound 61.2. Bis (pinacolate) diborate (0.9 g, 3.46 mmol,1.0 eq), PdCl₂(dppf) (0.277 g, 0.346 mmol, 0.1 eq) and AcOK (1.018 g,10.38 mmol, 3.0 eq) were dissolved in 1,4-dioxane (10 mL). Suspensionwas degassed using argon, then a solution of 61.1 (0.9 g, 3.46 mmol, 1.0eq) in 1,4-dioxane (8.0 mL) was added. Reaction mixture was stirred at70° C. for 3 hours. After completion of reaction, solids were filteredand solvents were removed under reduced pressure. The crude wassuspended in water then extracted with extracted with EtOAc. Organiclayers were combined, washed with brine solution, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude which was purifiedby column chromatography to furnish 61.2 (0.40 g, 37.6%).

Synthesis of compound 61.3. Compound 61.2 (0.4 g, 1.30 mmol, 1.0 eq),and DIBAL (5 mL, 0.51 mmol, 5.0 eq) were dissolved in CH₂Cl₂ (2.0 mL) at0° C. The reaction was stirred for 4 hours at 0-5° C. After completionof the reaction, MeOH was added and reaction mixture was stirred for 20minutes. Dilute HCl was added and the product was extracted with EtOAc.Organic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to provide crude 61.3 (0.36 g,99.0%), which was used in the next step without purification

Synthesis of compound 61.4. Compound 61.3 (0.36 g, 1.43 mmol, 1.0 eq)was dissolved in 6 M HCl (30 mL) and the reaction was stirred at 80° C.for 24 hours. After completion of the reaction, water was added to thereaction mixture and the product was extracted with EtOAc. Organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to furnish 1.3 (0.1 g, 43.3%).

Synthesis of compound 61.5. To a suspension of 10% Pd/C (0.25 g) in MeOH(5.0 mL) was added a solution of 61.4 (0.1 g, 0.3 mmol, 1.0 eq) in MeOH(3.0 mL) under nitrogen. Suspension was purged with H₂ gas for 1 hour.After completion of the reaction, mixture was filtered through celite,washed with MeOH and obtained filtrate was concentrated under reducedpressure to get crude material. The crude was purified by triturationwith n-hexane and Et₂O to provide 61.5 (0.060 g, 72.1%).

Synthesis of compound 61.6. To a mixture of 52.1 (0.06 g, 0.157 mmol,1.0 eq) in 1,4-dioxane (2.5 mL) was added 61.5 (0.025 g, 0.157 mmol, 1.0eq) and K₂CO₃ (0.067 g, 0.471 mmol, 3.0 eq). Mixture was degassed for 10minutes using argon, then Pd₂(dba)₃ (0.014 g, 0.015 mmol, 0.1 eq) andXantphos (0.016 g, 0.031 mmol, 0.2 eq) were added. Suspension wasdegassed for additional 5 minutes. The reaction was stirred at 100° C.for 2 hours. After completion of the reaction, mixture was poured intowater and product was extracted with EtOAc. Organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude material. The crude was purified usingcolumn chromatography to furnish 61.6 (0.027 g, 34.7%).

Synthesis of compound I-61. Compound 61.6 (0.027 g, 0.054 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (2.0 mL) and TFA (0.5 mL) was added to thereaction mixture. The reaction was stirred at room temperature for 1hour. After completion of the reaction, mixture was poured into water,basified with saturated NaHCO3 solution and extracted with EtOAc.Organic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by column chromatography to provide I-61 (0.006 g, 27.9%).¹H NMR (DMSO-d₆, 400 MHz): δ 9.12 (s, 1H), 8.61 (s, 1H), 7.48-7.37 (m,4H), 7.08-7.03 (m, 3H), 4.26 (s, 2H), 4.12 (s, 2H).

Example 62. Synthesis of4-((5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-62

Synthesis of compound 62.1. To a solution of 53.1 (0.3 g, 2.11 mmol, 1.0eq) in DMSO (10 mL) was added 1,4-dioxa-8-azaspiro[4.5]decane (0.30 g,2.11 mmol, 1.0 eq) followed by DIPEA (3.63 mL, 21.1 mmol, 10.0 eq). Thereaction mixture was stirred at 100° C. for 2 hours. After completion,reaction was quenched with water and product was extracted with EtOAc.Organic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain pure 62.1 (0.50 g, 89.3%).MS(ES): m/z 265.27 [M+H]⁺.

Synthesis of compound 62.2. To a suspension of 10% Pd/C (0.150 g) inMeOH (3.5 mL) was added a solution of 62.1 (0.5 g, 1.88 mmol, 1.0 eq) inMeOH (3.5 mL) under nitrogen. Suspension was purged using H₂ gas for 2hours. After completion of reaction, mixture was filtered through celiteand washed with MeOH. Solvents were removed under reduced pressure andthe crude was purified by trituration with n-pentane to provide 62.2(0.41 g, 92.5%). MS(ES): m/z 235.29 [M+H]⁺.

Synthesis of compound 62.3. To a solution of 52.1 (0.07 g, 0.184 mmol,1.0 eq) in 1,4-dioxane (3.0 mL) was added 62.2 (0.043 g, 0.184 mmol, 1.1eq) and K₂CO₃ (0.05 g, 0.368 mmol, 2.0 eq). Suspension was degassed for10 minutes using argon then Pd₂(dba)₃ (0.016 g, 0.018 mmol, 0.1 eq) andXantphos (0.021 g, 0.036 mmol, 0.2 eq) were added. After additional aronpurge (5 min), the reaction was stirred at 100° C. for 2 hours. Aftercompletion of the reaction, mixture was poured into water and mixturewas extracted with EtOAc. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified using columnchromatography to furnish 62.3 (0.068 g, 63.8%). MS(ES): m/z 579.60[M+H]⁺.

Synthesis of compound I-62. Compound 62.3 (0.068 g, 0.117 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (2.0 mL) and TFA (0.3 mL) was added to thereaction mixture. The reaction was stirred at room temperature for 1hour. After completion of the reaction, mixture was poured in water,basified with satd. NaHCO₃ solution and extracted with EtOAc. Organiclayers were combined, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude. The crude was purified by columnchromatography to furnish I-62 (0.039 g, 69.3%). MS(ES): m/z 479.49[M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.51 (s, 1H), 8.80 (s, 1H), 8.37(s, 1H), 8.05-8.04 (d, 1H), 7.60-7.53 (m, 1H), 7.49-7.46 (dd, 1H),7.28-7.22 (m, 2H), 7.15-7.07 (m, 1H), 4.40 (s, 2H), 3.90 (m, 4H),3.24-3.18 (m, 4H), 1.71-1.69 (t, 4H).

Example 63. Synthesis of2-(2,6-difluorophenyl)-4-((4-((3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-63

Synthesis of compound 63.1. To a solution of 54.2 (0.124 g, 0.668 mmol,1.0 eq) in THF (3.0 mL) was added Et₃N (0.202 g, 2.0 mmol, 3.0 eq) and(3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (0.1 g, 0.668 mmol, 1.0 eq)dropwise. The reaction was stirred at room temperature for 2 hours.After completion of the reaction, mixture was quenched with satd. NaHCO₃solution and product was extracted with EtOAc. Organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to obtain pure 63.1 (0.09 g, 53.1%). MS(ES): m/z 262.27[M+H]⁺.

Synthesis of compound 63.2. To a suspension of 10% Pd/C (0.050 g) inMeOH (3.5 mL) was added a solution of 63.1 (0.09 g, 0.343 mmol, 1.0 eq)in MeOH (2.5 mL) under N₂. Suspension was purged with H₂ gas for 1 hourAfter completion of the reaction, mixture was filtered through celite,washed with MeOH. Obtained filtrate was concentrated under reducedpressure to get pure 63.2 (0.06 g, 75.3%). MS(ES): m/z 232.28 [M+H]⁺.

Synthesis of compound 63.3. To a solution of 52.1 (0.065 g, 0.17 mmol,1.0 eq) in 1,4-dioxane (2.0 mL) was added 63.2 (0.040 g, 0.171 mmol, 1.0eq) and K₂CO₃ (0.047 g, 0.342 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.015 g, 0.017mmol, 0.1 eq) and Xantphos (0.020 g, 0.034 mmol, 0.2 eq) were added. Thereaction was stirred at 100° C. for 2 hours. After completion of thereaction, mixture was poured into water and product was extracted withEtOAc. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.The crude was purified by column chromatography to furnish 63.3 (0.065g, 66.0%). MS(ES): m/z 576.60 [M+H]⁺.

Synthesis of compound I-63. Compound 63.3 (0.065 g, 0.112 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (3.0 mL) and TFA (0.3 mL) was added to thereaction mixture. The reaction was stirred at room temperature for 1hour. After completion of the reaction, mixture was poured into water,basified with satd. NaHCO₃ and extracted with EtOAc. Organic layers werecombined, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by trituration withn-pentane and Et₂O to get pure I-63 (0.040 g, 74.5%). MS(ES): m/z 476.48[M+H]⁺; NMR (DMSO-d₆, 400 MHz): δ 9.17 (s, 1H), 8.78 (s, 1H), 7.56-7.50(m, 3H), 7.42-7.40 (d, 2H), 7.24-7.20 (t, 3H), 4.41 (s, 2H), 3.71 (m,4H), 3.46 (m, 4H), 2.89 (m, 2H).

Example 64. Synthesis of6-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)amino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one,I-64

Synthesis of compound 64.2. 2-Methane sulphonic acid (3.1 mL, 47.39mmol, 10.0 eq) was added to a mixture of 64.1 (1.0 g, 4.74 mmol, 1.0 eq)in CH₂Cl₂ (10.0 mL) at 0° C. Sodium azide (0.62 g, 9.48 mmol, 2.0 eq)was added slowly in portions. After completion of the addition, mixturewas stirred for additional 12 hours. After completion of reaction,aqueous mixture of NaOH (20%) was added until the mixture was slightlybasic. The mixture was extracted with CH₂Cl₂. Organic layers werecombined and solvents evaporated under reduced pressure. The crudematerial was purified by column chromatography to provide 64.2 (0.5 g,46.7%). MS(ES): m/z 226.07 [M+H]⁺.

Synthesis of compound 64.3. Compound 64.2 (0.5 g, 2.21 mmol, 1.0 eq) wasdissolved in DMF (3.5 mL) and NaH (0.076 g, 3.32 mmol, 1.5 eq) was addedto the reaction mixture at 0° C. Methyl iodide (0.47 g, 3.32 mmol, 1.5eq) was added to the reaction mixture dropwise at 0° C. The reaction wasstirred at 0° C. for 1 hour. After completion of the reaction, themixture was quenched with 2N HCl solution and the product was extractedwith EtOAc. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.The crude was purified by column chromatography to furnish 64.3 (0.25 g,47.1%). MS(ES): m/z 240.10 [M+H]⁺.

Synthesis of compound 64.4. To a solution of compound 64.3 (0.25 g, 1.04mmol, 1.0 eq) in toluene (1.0 mL) was added benzophenonimine (0.21 g,1.14 mmol, 1.1 eq) and NaOBu^(t) (0.15 g, 1.56 mmol, 1.5 eq). Themixture was degassed for 10 minutes using argon, then Pd₂(dba)₃ (0.009g, 0.01 mmol, 0.01 eq) and BINAP (0.029 g, 0.052 mmol, 0.05 eq) wereadded. The reaction was then heated at 100° C. for 8 hours. Aftercompletion, reaction mixture was poured into water and product wasextracted with EtOAc. Organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude material. The crude was purified by column chromatography toprovide 64.4 (0.04 g, 21.8%). MS(ES): m/z 176.22 [M+H]⁺.

Synthesis of compound 64.5. To a mixture of 52.1 (0.060 g, 0.157 mmol,1.0 eq) in 1,4-dioxane (1.5 mL) was added 64.4 (0.027 g, 0.157 mmol, 1.0eq) and K₂CO₃ (0.065 g, 0.47 mmol, 3.0 eq). The reaction mixture wasdegassed with argon for 10 minutes then Pd₂(dba)₃ (0.014 g, 0.015 mmol,0.1 eq) and Xantphos (0.018 g, 0.031 mmol, 0.2 eq) were added.Suspension was degassed again for 5 minutes. The reaction was stirred at100° C. for 2 hours. After completion of the reaction, mixture waspoured into water and product was extracted with EtOAc. Organic layerswere combined, washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude material. The crude was purifiedby column chromatography to provide 64.5 (0.038 g, 46.3%). MS(ES): m/z520.54 [M+H]⁺.

Synthesis of compound I-64. The compound 64.5 (0.038 g, 0.073 mmol, 1.0eq) was dissolved in CH₂Cl₂ (1.0 mL) and TFA (0.5 mL) was added to thereaction mixture. The reaction was stirred at room temperature for 1hour. After completion of reaction, mixture was poured into water,basified with satd. NaHCO₃ solution and product was extracted withEtOAc. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.The crude was purified by column chromatography to furnish I-64 (0.023g, 74.9%). MS(ES): m/z 420.42 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.23(s, 1H), 8.80 (s, 1H), 7.86-7.84 (d, 1H), 7.56-7.52 (m, 1H), 7.33-7.20(m, 5H), 4.41 (s, 2H), 3.55-3.51 (t, 2H), 3.00 (s, 3H), 2.99-2.95 (t,2H).

Example 65. Synthesis of4-((5-(2,5-dioxa-8-azaspiro[3.4]octan-8-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-65

Synthesis of compound 65.2. To a stirred solution of 2-aminoethan-1-ol(1.0 g, 16.37 mmol, 1.0 eq) in CH₂Cl₂ (10.0 mL) at room temperature wasadded 65.1 (1.29 g, 18.0 mmol, 1.1 eq), AcOH (0.098 g, 1.64 mmol, 0.1eq) and molecular sieves (1.0 g). The reaction was stirred at roomtemperature for 3 hours. After completion of the reaction, mixture wasfiltered, concentrated under reduced pressure. The crude was purified bycolumn chromatography to provide 65.2 (0.54 g, 33.8%). MS(ES): m/z115.13 [M+H]⁺.

Synthesis of compound 65.3. To a solution of 20.1 (0.5 g, 2.46 mmol, 1.0eq) in 1,4-dioxane (8.0 mL) were added compound 65.2 (0.283 g, 2.46mmol, 1.0 eq) and NaOBu^(t) (0.472 g, 4.92 mmol, 2.0 eq). The reactionmixture was degassed with argon gas for 15 minutes. Then Pd₂(dba)₃(0.023 g, 0.246 mmol, 0.1 eq) and Devphos (0.193 g, 0.492 mmol, 0.2 eq)were added to the reaction mixture. The reaction mixture was irradiatedin microwave at 100° C. for 2 hours. After completion of the reaction,mixture was quenched with water and the product was extracted withEtOAc. Organic layers were combined, washed with brine and concentratedunder reduced pressure to get crude material. The crude was purified bycolumn chromatography to provide 65.3 (0.165 g, 28.2%). MS(ES): m/z237.22 [M+H]⁺.

Synthesis of compound 65.4. To a suspension of 10% Pd/C (0.030 g) inMeOH (2.0 mL) was added a solution of 65.3 (0.165 g, 0.695 mmol, 1.0 eq)in MeOH (2.0 mL) under N₂. Suspension was purged with hydrogen gas for 1hour. After completion of the reaction, mixture was filtered throughcelite, washed with MeOH. Obtained filtrate was concentrated underreduced pressure and triturated with pentane to furnish 65.4 (0.14 g,97.1%). MS(ES): m/z 207.23 [M+H]⁺.

Synthesis of compound 65.6. To a suspension of 10% Pd/C (0.030 g) inMeOH (2.0 mL) was added a solution of 65.3 (0.165 g, 0.695 mmol, 1.0 eq)in MeOH (2.0 mL) under nitrogen atmosphere. Suspension was purged withH₂ gas for 1 hour. After completion of the reaction, mixture wasfiltered through celite, washed with MeOH. Solvents were removed under areduced pressure and the crude was triturated with pentane to get pure65.6 (0.14 g, 97.1%). MS(ES): m/z 207.23 [M+H]⁺.

Synthesis of compound I-65. Compound 65.6 (0.04 g, 0.07 mmol, 1.0 eq)was dissolved in THF/MeOH mixture (4:1) and LiOH (0.011 g, 0.282 mmol,4.0 eq) in water (1.0 mL) was added. The reaction was stirred at roomtemperature for 1 hour. After completion of the reaction, mixture waspoured into water, basified with satd. NaHCO₃ solution and product wasextracted with EtOAc. Organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude material. The crude was purified by trituration with Et₂O to getpure I-65 (0.022 g, 68.9%). MS(ES): m/z 451.43 [M+H]⁺; ¹H NMR (DMSO-d₆,400 MHz): δ 9.54 (s, 1H), 8.83 (s, 1H), 8.38 (s, 1H), 8.06 (d, 1H),7.58-7.55 (m, 2H), 7.27-7.22 (m, 3H), 5.04-5.02 (d, 2H), 4.69-4.67 (d,2H), 4.41 (s, 2H), 4.05-4.03 (m, 2H), 3.47-3.44 (m, 2H).

Example 66. Synthesis of2-(2,6-difluorophenyl)-4-((4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-propan-2-yl)phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-66

Synthesis of compound 66.1. To a mixture of 52.1 (0.070 g, 0.184 mmol,1.0 eq) in 1,4-dioxane (3.0 mL) was added2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.048 g, 0.184mmol, 1.0 eq) and K₂CO₃ (0.051 g, 0.368 mmol, 2.0 eq). Suspension wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.017 g, 0.018mmol, 0.1 eq) and Xantphos (0.021 g, 0.036 mmol, 0.2 eq) were added.Suspension was degassed for additional 5 minutes. The reaction wasstirred 100° C. for 2 hours. After completion of the reaction, mixturewas poured into water and product was extracted with EtOAc. Organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by column chromatography to furnish 66.1 (0.064 g, 57.7%).MS(ES): m/z 603.47 [M+H]⁺.

Synthesis of compound I-66. To a solution of 66.1 (0.064 g, 0.106 mmol,1.0 eq) in CH₂Cl₂ (1.5 mL) was added TFA (0.3 mL) at 0° C. Reactionmixture was stirred at room temperature for 1 hour. After completion ofthe reaction, mixture was poured into water, basified with satd. NaHCO₃and extracted with EtOAc. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude which was purified by trituration with Et₂O to furnish I-66(0.038 g, 71.8%). MS(ES): m/z 503.35 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz):δ 9.22 (s, 1H), 8.79 (s, 1H), 8.71 (s, 1H), 7.69-7.66 (d, 2H), 7.58-7.51(m, 3H), 7.24-7.19 (m, 3H), 4.41 (s, 2H).

Example 67. Synthesis of2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)amino)phenyl)-N-ethyl-2-methylpropanamide,I-67

Synthesis of compound 67.1. To a solution of NaOBu^(t) (1.45 g, 15.0mmol, 1.05 eq) in DMF (50 mL) at 0° C., was added 39.1 (3.0 g, 14.3mmol, 1.0 eq). After 5 minutes of stirring Mel (2.12 g, 15.0 mmol, 1.05eq) was added dropwise and the reaction mixture was stirred at 30minutes at 0° C. After 5 minutes second portion of NaOBu^(t) (1.45 g,15.0 mmol, 1.05 eq) was added at 0° C. and the reaction was stirred for5 minutes. Finally second portion of Mel (2.12 g, 15.0 mmol, 1.05 eq)was added dropwise and the reaction was stirred at 0° C. for 30 minutes.After completion, reaction was quenched with dilute AcOH and the productwas extracted with EtOAc. Organic layers were separated, combined,washed with brine solution, dried over Na₂SO₄ and concentrated underreduced pressure to get crude which was purified by columnchromatography to furnish 67.1 (2.0 g, 58.8%). MS (ES): m/z 237.26[M+H]⁺.

Synthesis of compound 67.2. To a solution of 67.1 (0.4 g, 1.68 mmol, 1.0eq) in THF (4.0 mL) was added ethyl amine (1.68 mL, 3.37 mmol, 2.0 eq)and DIPEA (0.6 mL, 3.36 mmol, 2.0 eq). The reaction was cooled to at 0°C. Trimethyl aluminium (4.2 mL, 8.4 mmol, 5.0 eq) was added dropwise at0° C. to the mixture then the reaction was stirred at reflux temperaturefor 6 hours. After completion, reaction mixture was quenched withchilled NaHCO₃ solution and the product was extracted with EtOAc.Organic layer was separated, washed with brine solution and concentratedunder reduced pressure to get crude material. The crude was purified bycolumn chromatography to provide 67.2 (0.24 g, 61.0%). MS(ES): m/z236.27 [M+H]⁺.

Synthesis of compound 67.3. To a suspension of 10% Pd/C (0.05 g) in MeOH(2.0 mL) was added a solution of 67.2 (0.243 g, 1.028 mmol, 1.0 eq) inMeOH (2.0 mL) under nitrogen. Hydrogen gas was bubbled into the reactionmixture for 1 hour at room temperature. After completion of thereaction, mixture was filtered through celite, washed with MeOH andobtained filtrate was concentrated under reduced pressure thentriturated with pentane to provide pure 67.3 (0.19 g, 89.6%). MS(ES):m/z 206.29 [M+H]⁺.

Synthesis of compound 67.4. To a mixture of 67.3 (0.1 g, 0.26 mmol, 1.0eq) in 1,4-dioxane (3.0 mL) was added compound 67.3 (0.06 g, 0.28 mmol,1.0 eq) and K₂CO₃ (0.090 g, 0.65 mmol, 2.5 eq). Reaction mixture wasdegassed for 10 minutes using argon then Pd₂(dba)₃ (0.024 g, 0.026 mmol,0.1 eq) and Xanthpos (0.03 g, 0.052 mmol, 0.2 eq) were added, and againdegassed for 5 minutes. The reaction was stirred at 100° C. for 2 hours.After completion of the reaction, mixture was poured into water andproduct was extracted with EtOAc. Organic layers were combined, washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude which was purified by column chromatography to provide 67.4(0.127 g, 87.8%). MS(ES): m/z 550.61 [M+H]⁺.

Synthesis of compound I-67. To a solution of 67.4 (0.127 g, 0.23 mmol,1.0 eq) in CH₂Cl₂ (2.0 mL) TFA (0.5 mL) was added. The reaction mixturewas stirred at room temperature for 1 hour. After completion of thereaction, mixture was basified with satd. saturated NaHCO₃ solution andextracted with EtOAc. Organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude which was purified by column chromatography and trituration withEt₂O to get pure I-67 (0.069 g, 66.4%). MS(ES): m/z 450.49 [M+H]⁺; ¹HNMR (DMSO-d₆, 400 MHz): δ 8.96 (s, 1H), 8.71 (s, 1H), 7.52 (m, 1H),7.37-7.31 (m, 5H), 7.22-7.18 (t, 2H), 7.02 (s, 1H), 4.38 (s, 2H),3.05-3.02 (q, 2H), 1.42 (s, 6H), 0.95-0.92 (t, 3H).

Example 68. Synthesis of4-(benzo[d][1,3]dioxol-5-ylamino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-68

Synthesis of compound 68.1. To a mixture of 52.1 (0.105 g, 0.394 mmol,1.0 eq) in 1,4-dioxane (2.0 mL) was added benzo[d][1,3]dioxol-5-amine(0.054 g, 0.394 mmol, 1.0 eq) and K₂CO₃ (0.11 g, 0.79 mmol, 2.0 eq). Thereaction was degassed using argon, then Pd₂(dba)₃ (0.036 g, 0.039 mmol,0.1 eq) and Xantphos (0.045 g, 0.078 mmol, 0.2 eq) were added. Thereaction was stirred at 100° C. for 2 hours. After completion of thereaction, mixture was poured into water and product was extracted withEtOAc. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.The crude was purified by column chromatography to provide 68.1 (0.105g, 55.4%). MS(ES): m/z 481.46 [M+H]⁺.

Synthesis of compound I-68. To a solution of 68.1 (0.10 g, 0.207 mmol,1.0 eq) in CH₂Cl₂ (2.0 mL) was added TFA (0.3 mL), dropwise at 0° C.under nitrogen. The reaction was stirred at room temperature for 1 hour.After completion of the reaction, mixture was poured into water,basified with satd. NaHCO₃ solution and extracted with EtOAc. Organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by trituration with pentane to get pure I-68 (0.075 g,94.7%). MS(ES): m/z 381.34 [M+H]⁺; NMR (DMSO-d₆, 400 MHz): δ 8.74 (s,1H), 8.65 (s, 1H), 7.53-7.49 (m, 1H), 7.21-7.17 (t, 2H), 6.98-6.92 (m,2H), 6.82-6.79 (m, 2H), 6.04 (s, 2H), 4.37 (s, 2H).

Example 69. Synthesis of4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-2-(2,6-difluoro-phenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-69

Synthesis of compound 69.2. To a suspension of 10% Pd/C (0.05 g) in MeOH(5.0 mL) was added a solution of 69.1 (0.5 g, 2.46 mmol, 1.0 eq) in MeOH(3.0 mL) under nitrogen. Reaction was purged with H₂ gas for 2 hours.After completion of the reaction, mixture was filtered through celiteand washed with MeOH. Obtained filtrate was concentrated under reducedpressure to get crude which was purified by trituration with n-hexane toprovide 69.2 (0.31 g, 72.5%). MS(ES): m/z 173.12 [M+H]⁺.

Synthesis of compound 65.5. A solution of NaH (0.01, 3.57 mmol, 2.0 eq)in THF (10 mL) was cooled to 0° C. Compound 69.3 (0.5 g, 1.78 mmol, 1.0eq) was added and stirred at 0° C. Methyl pivaloyl chloride (0.321 g,2.14 mmol, 1.2 eq) was added dropwise and the reaction was stirred atroom temperature for 4 hours. After completion, the reaction wasquenched with water. Product was extracted with EtOAc and washed withNaHCO₃ solution. Organic layer was separated, washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure to get crude. Thecrude was purified by column chromatography to furnish 65.5 (0.34 g,58.4%). MS(ES): m/z 326.62 [M+H]⁺.

Synthesis of compound 69.4. To a solution of compound 65.5 (0.12 g,0.225 mmol, 1.0 eq) in 1,4-dioxane (3.0 mL) was added compound 69.2(0.039 g, 0.223 mmol, 1.0 eq) and K₂CO₃ (0.077 g, 0.564 mmol, 2.5 eq).Suspension was degassed for 10 minutes using argon, then Pd₂(dba)₃(0.021 g, 0.023 mmol, 0.1 eq) and Xantphos (0.026 g, 0.045 mmol, 0.2 eq)were added and again degassed for 5 minutes. The reaction was stirred at100° C. for 2 hours. After completion of the reaction, mixture waspoured into water and extracted with EtOAc. Organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to provide 69.4 (0.12 g, 69.3%). MS(ES): m/z 463.28[M+H]⁺.

Synthesis of compound I-69. To a solution of compound 69.4 (0.12 g, 0.25mmol, 1.0 eq) in CH₂Cl₂ (3.0 mL) was added TFA (1.5 mL). The reactionwas stirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into water, basified with satd. NaHCO₃solution and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude which was purified by columnchromatography and trituration to furnish I-69 (0.037 g, 34.8%). MS(ES):m/z 417.32 [M+H]⁺; NMR (DMSO-d₆, 400 MHz): δ 8.98 (s, 1H), 8.71 (s, 1H),7.54-7.41 (m, 3H), 7.21-7.17 (m, 3H), 6.97 (s, 1H), 4.39 (s, 2H).

Example 70. Synthesis of2-(2,6-difluorophenyl)-4-((3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-70

Synthesis of compound 70.1. To a mixture of 52.1 (0.1 g, 0.26 mmol, 1.0eq) in 1,4-dioxane (3.0 mL) was added3,3-dimethyl-2,3-dihydrobenzofuran-6-amine (0.042 g, 0.262 mmol, 1.0 eq)and K₂CO₃ (0.09 g, 0.657 mmol, 2.5 eq). The reaction mixture wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.024 g, 0.026mmol, 0.1 eq) and Xantphos (0.030 g, 0.052 mmol, 0.2 eq) were added.Suspension was then degassed for additional 5 minutes. The reaction wasthen heated at 100° C. for 2 hours. After completion of the reaction,mixture was poured into water and product was extracted with EtOAc.Organic layers were combined, washed with brine solution, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.This crude was purified by column chromatography to furnish 70.1 (0.076g, 57.0%). MS(ES): m/z 507.54 [M+H]⁺.

Synthesis of compound I-70. A solution of 70.1 (0.076 g, 0.149 mmol, 1.0eq) in CH₂Cl₂ (3.0 mL) was added TFA (1.0 mL). The reaction was stirredat room temperature for 1 hour. After completion of the reaction,mixture was poured into water, basified with satd. NaHCO₃ solution andproduct was extracted with EtOAc. Organic layers were combined, washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude. The crude was purified by column chromatography andtrituration to furnish I-70 (0.05 g, 82.0%). MS(ES): m/z 407.42 [M+H]⁺;¹H NMR (DMSO-d₆, 400 MHz): δ 8.88 (s, 1H), 8.69 (s, 1H), 7.56-7.49 (m,1H), 7.23-7.18 (m, 3H), 7.00 (s, 1H), 6.85-6.82 (dd, 1H), 6.78-6.77 (d,1H), 4.37 (s, 2H) 4.23 (s, 2H), 1.28 (s, 6H).

Example 71. Synthesis of2-(2,6-difluorophenyl)-4-((2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-71

Synthesis of compound 71.2. To a mixture of 71.1 (2.13 g, 12.3 mmol, 1.0eq) and K₂CO₃ (3.4 g, 24.6 mmol, 2.0 eq) in DMF (10 mL) at roomtemperature, was added 3-bromo-2-methylprop-1-ene (2.0 g, 14.8 mmol, 1.2eq). Reaction mixture was stirred at 80° C. for 3 hours. Aftercompletion of the reaction, mixture was poured into water and extractedwith EtOAc. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to provide 71.2 (2.9 g,99.0%). MS(ES): m/z 227.10 [M+H]⁺.

Synthesis of compound 71.3. A solution of 71.2 (2.9 g, 12.8 mmol, 1.0eq) in N,N-diethyl aniline (10 mL) was stirred under argon at 210-220°C. for 12 hours. After completion of the reaction, mixture was cooled toroom temperature, acidified with 1N HCl extracted with EtOAc. Organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by column chromatography to provide 71.3 (0.55 g, 18.9%).MS(ES): m/z 227.10 [M+H]⁺.

Synthesis of compound 71.4. To a solution of compound 71.3 (0.55 g, 2.43mmol, 1.0 eq) in dry toluene (6.0 mL), p-toluene sulphonic acid (46 mL)was added. Reaction mixture was stirred at 100° C. for 2 hours. Aftercompletion of the reaction, mixture was cooled to room temperature andbasified with 1N NaOH solution and extracted with EtOAc. Organic layerswere combined, washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude which was purified by columnchromatography to provide 71.4 (0.45 g, 81.8%). MS(ES): m/z 227.10[M+H]⁺.

Synthesis of compound 71.5. To a solution of 71.4 (0.25 g, 1.10 mmol,1.0 eq) in THF (5.0 mL) was added CyJohnphos (0.077 g, 0.22 mmol, 0.2eq) and Pd₂(dba)₃ (0.1 g, 0.11 mmol, 0.1 eq). Suspension was degassedwith argon, LHMDS (0.919 g, 5.50 mmol, 5.0 eq) was added and the mixturewas stirred at 100° C. for 2 hours. After completion of the reaction,mixture was poured into dilute HCl and extracted with EtOAc. Aqueousfractions were basified with saturated NaHCO₃ solution and extractedwith EtOAc. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude. Thecrude was purified by column chromatography to provide 71.5 (0.087 g,48.4%). MS(ES): m/z 163.22 [M+H]⁺.

Synthesis of compound 71.6. To a mixture of 52.1 (0.11 g, 0.29 mmol,1.15 eq) in 1,4-dioxane (2.5 mL) was added compound 1.4 (0.042 g, 0.251mmol, 1.0 eq) and K₂CO₃ (0.069 g, 0.502 mmol, 2.0 eq). The reactionmixture was degassed for 10 minutes using argon, then Pd₂(dba)₃ (0.023g, 0.021 mmol, 0.1 eq) and Xantphos (0.029 g, 0.050 mmol, 0.2 eq) wereadded, and again degassed for 5 minutes. Reaction was stirred at 100° C.for 2 hours. After completion of the reaction, mixture was poured intowater and extracted with EtOAc. Organic layers were combined, washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by column chromatographyto furnish 71.6 (0.095 g, 64.8%). MS(ES): m/z 507.54 [M+H]⁺.

Synthesis of compound I-71. To a solution of compound 71.6 (0.095 g,0.187 mmol, 1.0 eq) in CH₂Cl₂ (2.0 mL) was added TFA (0.5 mL). Thereaction was stirred at room temperature for 1 hour. After completion ofthe reaction, mixture was poured into water, basified with satd. NaHCO₃and extracted with EtOAc. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude which was purified by column chromatography to provide I-71(0.041 g, 53.8%). MS(ES): m/z 407.42 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz): δ8.67 (s, 1H), 7.39-7.31 (m, 1H), 7.14-7.10 (m, 2H), 7.02-6.96 (m, 2H),6.77-6.74 (dd, 1H), 6.71-6.70 (d, 1H), 5.98 (s, 1H), 4.50 (s, 2H), 3.01(s, 2H), 1.50 (s, 6H).

Example 72. Synthesis of2-(2,6-difluorophenyl)-4-((4-oxochroman-7-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-72

Synthesis of compound 72.2. To a solution of 72.1 (1.0 g, 6.7 mmol, 1.0eq) in concentrated H₂SO₄ (20 mL) was added a solution of KNO₃ (0.75 g,7.4 mmol, 1.1 eq) in sulphuric acid (13 mL) at 0° C. The reaction wasstirred at 0° C. for 1 hour. After completion of the reaction, mixturewas poured into ice-water. White precipitate was filtered off, washedwith water and dried. Solids were triturated with EtOAc, filtered anddried under vacuum to get 72.1 (1.0 g, 76.7%). MS(ES): m/z 193.16[M+H]⁺.

Synthesis of compound 72.3. To a suspension of compound 72.1 (0.1 g, 0.5mmol, 1.0 eq) in MeOH (4.0 mL) and water (1.0 mL) was added NH₄Cl (0.26g, 5.0 mmol, 10 eq) and iron powder (0.28 g, 5 mmol, 10 eq). Thereaction was stirred at reflux for 2 hours. After completion of thereaction, mixture was partioned between water and EtOAC, filteredthrough celite. Organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure to obtain crude. The crude was purified by columnchromatography to provide 72.3 (0.065 g, 76.9%). MS(ES): m/z 163.18[M+H]⁺.

Synthesis of compound 72.4. To a mixture of 52.1 (0.1 g, 0.262 mmol, 1.0eq) in 1,4-dioxane (2.5 mL) was added compound 72.3 (0.051 g, 0.315mmol, 1.2 eq) and K₂CO₃ (0.054 g, 0.363 mmol, 1.5 eq). Mixture wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.024 g, 0.026mmol, 0.1 eq) and Xantphos (0.03 g, 0.052 mmol, 0.2 eq) were added andagain degassed for 5 minutes. The reaction was stirred at 100° C. for 2hours. After completion of the reaction, mixture was poured into waterand product was extracted with EtOAc. Organic layers were combined,washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude material. The crude was purified by columnchromatography to furnish 72.4 (0.10 g, 77.3%). MS(ES): m/z 507.49[M+H]⁺.

Synthesis of compound I-72. To a solution of 72.4 (0.103 g, 0.202 mmol,1.0 eq) in CH₂Cl₂ (3.0 mL) was added TFA (1.0 mL). Reaction mixture wasstirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into water, basified with satd. NaHCO₃ andextracted with EtOAc. Organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to obtain thecrude which was purified by column chromatography to furnish I-72 (0.070g, 84.7%). MS(ES): m/z 407.38 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 8.89(s, 1H), 8.67 (s, 1H), 7.67-7.66 (d, 1H), 7.57-7.47 (m, 2H), 7.21-7.17(t, 2H), 7.11-7.08 (d, 1H), 6.76 (s, 1H), 4.56-4.53 (t, 2H), 4.38 (s,2H), 2.81-2.78 (t, 2H).

Example 73. Synthesis of2-(2,6-difluorophenyl)-4-((6-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-3-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-73

Synthesis of compound 73.2. To a stirred solution of 73.1 (0.19 g, 1.336mmol, 1.0 eq) and (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (0.2 g, 1.34mmol, 1.0 eq) in dry DMSO (5.0 mL), was added DIPEA (2.37 mL, 13.36mmol, 10.0 eq). The reaction was stirred at 110° C. for 2 hours. Aftercompletion of the reaction, mixture was poured into water and extractedwith EtOAc. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.The crude was purified by trituration to afford 73.2 (0.24 g, 76.3%).MS(ES): m/z 235.24 [M+H]⁺.

Synthesis of compound 73.3. To a suspension of 10% Pd/C (0.15 g) in MeOH(2.5 mL) was added a solution of compound 73.2 (0.24 g, 1.02 mmol, 1.0eq) in MeOH (2.5 mL) under nitrogen. H₂ gas was bubbled into thereaction mixture for 2 hours. After completion of the reaction, mixturewas filtered through celite, washed with MeOH. Obtained filtrate wasconcentrated under reduced pressure to get crude which was purified bycolumn chromatography to furnish 73.3 (0.15 g, 71.6%). MS(ES): m/z205.26 [M+H]⁺.

Synthesis of compound 73.4. To a mixture of 52.1 (0.1 g, 0.263 mmol, 1.2eq) in 1,4-dioxane (3.0 mL) was added compound 73.3 (0.045 g, 0.219mmol, 1.0 eq) and K₂CO₃ (0.06 g, 0.438 mmol, 2.0 eq). The reaction wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.02 g, 0.021 mmol,0.1 eq) and Xantphos (0.025 g, 0.043 mmol, 0.2 eq) were added. Thereaction was stirred at 100° C. for 2 hours. After completion of thereaction, mixture was poured into the water and product was extractedwith EtOAc. Organic layers were combined, washed with brine solution,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude material which was purified by column chromatography to furnish73.4 (0.1 g, 69.3%). MS(ES): m/z 549.58 [M+H]⁺.

Synthesis of compound I-73. To a solution of compound 73.4 (0.1 g, 0.18mmol, 1.0 eq) in CH₂Cl₂ (3.0 mL) was added TFA (0.4 mL). The reactionwas stirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into water, basified with satd. NaHCO₃solution and extracted with EtOAc. Organic layer were combined, washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material which was purified by trituration with n-pentaneand Et₂O to get pure I-73 (0.055 g, 67.3%). MS(ES): m/z 449.46 [M+H]⁺;¹H NMR (DMSO-d₆, 400 MHz): δ 8.61-8.59 (d, 1H), 8.08-8.07 (d, 1H),7.53-7.46 (m, 2H), 7.19-7.15 (t, 2H), 6.56-6.53 (m, 2H), 4.36 (s, 2H),3.86-3.82 (m, 2H), 3.56-3.51 (m, 4H), 3.33-3.32 (m, 2H), 3.00 (m, 2H).

Example 74. Synthesis of3-fluoro-2-(5-oxo-4-((6-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-3-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile,I-74

Synthesis of compound 74.2. To a mixture of 74.1 (0.08 g, 0.206 mmol,1.2 eq) in 1,4-dioxane (2.5 mL) was added 73.3 (0.035 g, 0.172 mmol, 1.0eq) and K₂CO₃ (0.048 g, 0.344 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.016 g, 0.017mmol, 0.1 eq) and Xantphos (0.02 g, 0.034 mmol, 0.2 eq) were added andagain degassed for 5 minutes. The reaction was stirred at 100° C. for 2hours. After completion of the reaction, mixture was poured into waterand product was extracted with EtOAc. Organic layers were combined,washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude which was purified by column chromatography tofurnish 74.2 (0.075 g, 65.3%). MS(ES): m/z 556.60 [M+H]⁺.

Synthesis of compound I-74. A solution of compound 74.3 (0.075 g, 0.134mmol, 1.0 eq) in CH₂Cl₂ (3.0 mL) was added TFA (0.4 mL). The mixture wasstirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into water, basified with satd. NaHCO₃ andextracted with EtOAc. Organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude material. The crude was purified by trituration with n-hexane andEt₂O to provide (0.03 g, 48.8%). MS(ES): m/z 456.48 [M+H]⁺; ¹H NMR(MeOD, 400 MHz): δ 8.10 (d, 1H), 7.72-7.55 (m, 4H), 6.75 (s, 1H),6.67-6.65 (d, 1H), 4.48 (s, 2H), 4.00-3.96 (m, 2H), 3.72-3.65 (m, 4H),3.44-3.43 (m, 2H), 3.15-3.12 (m, 2H).

Example 75. Synthesis of2-(4-((5-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3-fluorobenzonitrile,I-75

Synthesis of compound 75.1. To a mixture of 74.1 (0.075 g, 0.193 mmol,1.0 eq) in 1,4-dioxane (2.5 mL) was added compound 20.3 (0.043 g, 0.212mmol, 1.1 eq) and K₂CO₃ (0.080 g, 0.579 mmol, 3.0 eq). The mixture wasdegassed with argon then Pd₂(dba)₃ (0.018 g, 0.019 mmol, 0.1 eq) andXantphos (0.022 g, 0.039 mmol, 0.2 eq) were added, again degassed for 5min. The reaction was then heated at 100° C. for 0.5 h. After completionof the reaction, mixture was poured into water and extracted with EtOAc.Organic layers were combined, washed with brine solution, dried overNa₂SO₄ and concentrated under reduced pressure to obtain the crude whichwas purified by column chromatography to provide 75.1 (0.05 g, 46.6%).MS(ES): m/z 555.6 [M+H]⁺.

Synthesis of compound I-75. A solution of 75.1 (0.05 g, 0.09 mmol, 1.0eq) in CH₂Cl₂ (1.0 mL) was added TFA (0.2 mL). The mixture was stirredat room temperature for 1 hour. After completion of the reaction,mixture was poured into water, basified with satd. NaHCO₃ solution andextracted with EtOAc. Organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude which was purified by column chromatography to furnish I-75 (0.04g, 97.6%). MS(ES): m/z 455.57 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz): δ 9.41(s, 1H), 8.65-8.64 (d, 1H), 8.07-8.06 (d, 1H), 7.64-7.63 (d, 1H),7.55-7.43 (m, 2H), 7.35-7.32 (dd, 1H), 6.94-6.92 (d, 1H), 6.19 (s, 1H),4.55 (s, 2H), 3.23-3.20 (t, 4H), 1.56-1.53 (t, 4H), 0.48 (s, 4H).

Example 76. Synthesis of3-fluoro-2-(5-oxo-4-((5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile,I-76

Synthesis of compound 76.1. To a mixture of 74.1 (0.1 g, 0.258 mmol, 1.0eq) in 1,4-dioxane (3.0 mL) was added 59.2 (0.052 g, 0.258 mmol, 1.0 eq)and K₂CO₃ (0.089 g, 0.645 mmol, 2.5 eq). The reaction mixture wasdegassed for 10 minutes using argon then Pd₂(dba)₃ (0.023 g, 0.025 mmol,0.1 eq) and Xantphos (0.029 g, 0.051 mmol, 0.2 eq) were added, and againdegassed for 5 minutes. The reaction was stirred at 100° C. for 2 hours.After completion of the reaction, mixture was poured into water andproduct was extracted with EtOAc. Organic layers were combined, washedwith brine solution, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude material. The crude was purified by columnchromatography to get pure 76.1 (0.075 g, 52.3%). MS(ES): m/z 556.60[M+H]⁺.

Synthesis of compound I-76. Compound 76.1 (0.075 g, 0.134 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (2.0 mL) and TFA (0.3 mL) was added. Thereaction was stirred at room temperature for 1 hour. After completion ofthe reaction, mixture was poured into water, basified with satd. NaHCO₃solution and product was extracted with EtOAc. Organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude material. The crude was purified bycolumn chromatography to get pure I-76 (0.027 g, 43.9%). MS(ES): m/z456.48 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz): δ 9.48 (s, 1H), 8.84 (s, 1H),8.39 (s, 1H), 7.88-7.86 (dd, 1H), 7.80-7.71 (m, 3H), 7.18-7.11 (m, 2H),4.41 (s, 2H), 3.87-3.83 (dd, 2H), 3.53-3.50 (dd, 2H), 3.34-3.28 (m, 2H),3.20-3.17 (dd, 2H), 2.98 (m, H).

Example 77. Synthesis of2-(2,6-difluorophenyl)-4-((3-oxo-3H-spiro[benzofuran-2,1′-cyclopropan]-6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-61

Synthesis of 77.2. Compound 77.1 (2.0 g, 12.0 mmol, 1.0 eq) in EtOAc (30mL) was added to a cooled solution of NaHCO₃ (1.38 g, 16.4 mmol, 1.37eq) in water (15 mL). The reaction was stirred for 10 minutes. Acetylchloride (1.28 g, 16.4 mmol, 1.37 eq) was added to the mixture over 15minutes and the reaction was stirred at room temperature for 2 hours.After completion of the reaction, mixture was quenched with water andextracted with EtOAc. Organic layers were combined, washed with satd.NaHCO₃, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by trituration with EtOAcand n-hexane to furnish 77.2 (2.2 g, 87.9%). MS(ES): m/z 209.20 [M+H]⁺.

Synthesis of 77.3. To a solution of compound 77.2 (2.2 g, 10.5 mmol, 1.0eq) in acetone (5.5 mL) was added K₂CO₃ (1.8 g, 13.1 mmol, 1.25 eq) and3-bromodihydrofuran-2(3H)-one (2.3 g, 14 mmol, 1.33 eq). The reactionwas stirred at 60° C. for two days. After completion of the reaction,mixture was cooled to room temperature and the product was filteredthrough celite. The celite bed was washed with acetone and the filtratewas concentrated under reduced pressure to get crude material. The crudewas purified by column chromatography to furnish 77.3 (0.70 g, 22.7%).MS(ES): m/z 294.28 [M+H]⁺.

Synthesis of 77.4. To the mixture of 77.3 (0.5 g, 1.7 mmol, 1.0 eq) andAc₂O (7.5 mL) was added Et₃N (1.5 mL). Reaction was stirred at refluxfor 12 hours. After completion of the reaction, mixture was quenchedwith water and product was extracted with EtOAc. Organic layers werecombined, washed with satd. NaHCO₃ and brine solutions, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.The crude was purified by column chromatography to furnish 77.4 (0.21 g,47.2%). MS(ES): m/z 262.23 [M+H]⁺.

Synthesis of 77.5. To a solution of 77.4 (0.2 g, 0.76 mmol, 1.0 veq) inDMSO (0.5 mL) was added NaCl (0.009 g, 0.167 mmol, 0.22 eq). Reactionmixture was heated to 150° C. for 1 hour. After completion of thereaction, mixture was quenched with water and product was extracted withEtOAc. Organic layers were combined, washed with satd. NaHCO₃ and brinesolutions, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by trituration withn-hexane to provide pure 77.5 (0.115 g, 69.2%). MS(ES): m/z 217.22[M+H]⁺.

Synthesis of 77.6. To a solution of 77.5 (0.1 g, 0.46 mmol, 1.0 eq) inMeOH (2.0 mL) and was added KOH (0.077 g, 1.38 mmol, 3.0 eq). Thereaction mixture was stirred at 65° C. for 2 hours. After completion ofthe reaction, mixture was quenched with water and product was extractedwith EtOAc. Organic layers were combined washed with satd. NaHCO₃ andbrine solutions, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude which was purified by trituration with n-hexaneto get pure 77.6 (0.074 g, 91.8%). MS(ES): m/z 175.19 [M+H]⁺.

Synthesis of 77.7. To a mixture of 52.1 (0.085 g, 0.22 mmol, 1.0 eq) in1,4-dioxane (2.0 mL) was added compound 77.6 (0.039 g, 0.22 mmol, 1.0eq) and K₂CO₃ (0.06 g, 0.44 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.022 g, 0.022mmol, 0.1 eq) and Xantphos (0.025 g, 0.044 mmol, 0.2 eq) were added.Suspension was degassed for additional 5 minutes. The reaction wasstirred at 100° C. for 2 hours. After completion of the reaction,mixture was poured into water and product was extracted with EtOAc.Organic layers were combined, washed with brine solution, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude which waspurified by column chromatography to furnish 77.7 (0.081 g, 69.9%).MS(ES): m/z 519.50 [M+H]⁺.

Synthesis of I-77. To a solution of compound 77.7 (0.081 g, 0.153 mmol,1.0 eq) in CH₂Cl₂ (1.0 mL) was added TFA (0.5 mL). The reaction wasstirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into water, basified with satd. NaHCO₃solution and extracted with EtOAc. Organic layers were combined, driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudematerial. The crude was purified by trituration with w-pentane tofurnish I-77 (0.049 g, 75.9%). MS(ES): m/z 419.39 [M+H]⁺; ¹H NMR(DMSO-d₆, 400 MHz): δ 9.53 (s, 1H), 8.88 (s, 1H), 7.67-7.65 (d, 1H),7.58-7.50 (m, 2H), 7.32 (d, 1H), 7.26-7.16 (m, 3H), 4.45 (s, 2H),1.76-1.73 (q, 2H), 1.42-1.39 (q, 2H).

Example 78. Synthesis of2-(2,6-difluorophenyl)-4-((5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-78

Synthesis of compound 78.2. Compound 78.1 (1.0 g, 6.0 mmol, 1.0 eq) wasdissolved in THF (10.0 mL) and cooled to 0° C. Trimethyl(trifluoromethyl) silane (1.27 g, 9.0 mmol, 1.5 eq) and TBAF (0.120 g,1.2 mmol, 0.02 eq) were added to the mixture. Reaction was stirred atroom temperature for 24 hours. After completion of the reaction, mixturewas quenched with 2N HCl solution and extracted with EtOAc. Organiclayers were combined, washed with brine dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude material. The crudewas purified by column chromatography to provide 78.2 (0.95 g, 65.5%).MS(ES): m/z 225.60 [M+H]⁺.

Synthesis of compound 78.3. To a solution of 78.2 (0.45 g, 1.99 mmol,1.0 eq) in THF (5.0 mL) (2-biphenyl)dicyclohexylphosphine (0.14 g, 0.4mmol, 0.2 eq) and Pd2(dba)3 (0.182 g, 0.2 mmol, 0.1 eq) were added. Thereaction was degassed with argon for 30 minutes. LHMDS (12 mmol, 6.0 eq)was added and the reaction was stirred at reflux temperature for 6hours. After completion of the reaction, mixture was quenched with coldHCl solution and extracted with EtOAc. Aqueous layer were combined,basified with NaHCO₃, and extracted with EtOAc. Organic layer was washedwith water, brine and dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude. The crude was purified by trituration withEt₂O to furnish 78.3 (0.52 g, 99.0%). MS(ES): m/z 206.17 [M+H]⁺.

Synthesis of compound 78.4. To a mixture of 53.1 (0.250 g, 0.65 mmol,1.0 eq) in 1,4-dioxane (2.5 mL) was added 78.3 (0.135 g, 0.65 mmol, 1.0eq) and K₂CO₃ (0.180 g, 1.3 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 minutes using argon, then Pd₂(dba)₃ (0.060 g, 0.065mmol, 0.1 eq) and Xantphos (0.075 g, 0.13 mmol, 0.2 eq) were added, andagain degassed for 5 minutes. The reaction was stirred at 100° C. for 2hours. After completion of the reaction, mixture was poured into waterand product was extracted with EtOAc. Organic layers were combined,washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude material. The crude was purified by columnchromatography to furnish 78.4 (0.23 g, 63.6%). MS(ES): m/z 550.49[M+H]⁺.

Synthesis of compound I-78. To a solution of compound 78.4 (0.21 g,0.381 mmol, 1.0 eq) in CH₂Cl₂ (2.0 mL) was added TFA (0.5 mL). Thereaction mixture was stirred at room temperature for 1 hour. Aftercompletion of the reaction, mixture was poured into water, basified withsatd. NaHCO₃ solution and product was extracted with EtOAc. Organiclayers were combined, washed with brine solution, dried over Na₂SO₄ andconcentrated under reduced pressure to obtain crude which was purifiedby trituration to furnish I-78 (0.17 g, 98.9%). MS(ES): m/z 450.37[M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.83 (s, 1H), 8.93 (s, 1H), 8.62(s, 1H), 8.51 (d, 1H), 7.95-7.93 (t, 1H), 7.60-7.56 (m, 1H), 7.29-7.20(m, 3H), 6.74 (s, 1H), 4.45 (s, 2H), 1.70 (s, 3H).

Example 79. Synthesis of2-(4-((6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-3-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3-fluorobenzonitrile,I-79

Synthesis of compound 79.2. To a mixture 79.1 (0.019 g, 0.121 mmol, 1.0eq) in EtOAc (2.0 mL) was added 4-oxa-7-azaspiro[2.5]octane (0.02 g,0.133 mmol, 1.1 eq) and Et₃N (0.031 g, 0.29 mmol, 2.4 eq). The reactionwas stirred at 80° C. for 3 hours. After completion of the reaction,solvent was evaporated under reduced pressure. The residue wastriturated with 0.2% dichloromethane in hexane to provide 79.2 (0.054 g,99.0%). MS(ES): m/z 236.27 [M+H]⁺.

Synthesis of compound 79.3. To a suspension of 10% Pd/C (0.030 g) inMeOH (2.0 mL) was added a solution of compound 79.2 (0.054 g, 0.229mmol, 1.0 eq) in MeOH (2.0 mL) under nitrogen. Reaction was purged withH₂ gas for 1 hour. After completion of the reaction, mixture wasfiltered through celite, washed with MeOH. Filtrate was concentratedunder reduced pressure. The residue was triturated with 0.5% CH₂Cl₂ inhexane to provide pure 79.3 (0.047 g, 99.0%)

Synthesis of compound 79.4. To a mixture of 74.1 (0.075 g, 0.193 mmol,1.0 eq) in 1,4-dioxane (3.0 ml) was added 79.3 (0.044 g, 0.212 mmol, 1.0eq) and K₂CO₃ (0.08 g, 0.579 mmol, 3.0 eq). Mixture was degassed for 10minutes using argon, then Pd₂(dba)₃ (0.017 g, 0.019 mmol, 0.1 eq) andXantphos (0.022 g, 0.038 mmol, 0.2 eq) were added. Reaction mixture wasdegassed for additional 5 minutes then stirred at 100° C. for 2 hours.After completion of the reaction, mixture was poured into water andproduct was extracted with EtOAc. Organic layers were combined, washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by column chromatographyto furnish 79.4 (0.05 g, 46.5%). MS(ES): m/z 557.78 [M+H]⁺.

Synthesis of compound I-79. To a solution of 79.4 (0.050 g, 0.089 mmol,1.0 eq) in CH₂Cl₂ (2.0 mL) was added TFA (0.5 mL) The reaction wasstirred at room temperature for 1.5 hours. After completion of thereaction, mixture was poured into water, basified with satd. NaHCO₃ andextracted with EtOAc. Organic layers were combined, dried over Na₂SO₄and concentrated under reduced pressure to obtain crude. The crude waspurified by column chromatography to furnish I-79 (0.025 g, 61.0%).MS(ES): m/z 457.57 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz): δ 8.42 (s, 1H),8.22-8.21 (d, 1H), 7.60-7.58 (d, 1H), 7.54-7.37 (m, 3H), 6.81 (s, 1H),6.70-6.68 (d, 1H), 6.18 (s, 1H), 4.54 (s, 2H), 3.93-3.90 (t, 2H),3.67-3.64 (t, 2H), 3.51 (s, 2H), 0.86 (t, 2H), 0.56 (t, 2H).

Example 80. Synthesis of2-(4-((3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3-fluorobenzonitrile,I-80

Synthesis of compound 80.1. To a solution of 74.1 (0.1 g, 0.25 mmol, 1.0eq) in 1,4-dioxane (2.5 mL) was added3,3-dimethyl-2,3-dihydrobenzofuran-6-amine (0.041 g, 0.25 mmol, 1.0 eq)and K₂CO₃ (0.069 g, 0.5 mmol, 2.0 eq). After degassing with argon (10minutes), Pd₂(dba)₃ (0.022 g, 0.025 mmol, 0.1 eq) and Xantphos (0.029 g,0.05 mmol, 0.2 eq) were added. Suspension was degassed with argon foraddition 5 minutes, then stirred at 100° C. for 2 hours. Aftercompletion of the reaction, mixture was poured into water and extractedwith EtOAc. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain the crude. Thecrude was purified by column chromatography to furnish 80.1 (0.065 g,49.0%). MS(ES): m/z 514.56 [M+H]⁺.

Synthesis of compound I-80. To a solution of 80.1 (0.065 g, 0.126 mmol,1.0 eq) in CH₂Cl₂ (2.0 mL) was added TFA (0.5 mL). The reaction mixturewas stirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into iced water, basified with NaHCO₃ andextracted with EtOAc. Organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude material. The crude was purified by column chromatography toprovide I-80 (0.026 g, 49.7%). MS(ES): m/z 414.44 [M+H]⁺; ¹H NMR(DMSO-d₆, 400 MHz): δ 8.96 (s, 1H), 8.75 (s, 1H), 7.85-7.83 (m, 1H),7.72-7.70 (m, 2H), 7.22-7.17 (m, 2H), 6.88-6.62 (m, 2H), 4.40 (s, 2H),4.24 (s, 2H), 1.29 (s, 6H).

Example 81. Synthesis of2-(4-((2-(2-cyano-6-fluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)amino)phenyl)-N-ethyl-2-methylpropanamide,I-81

Synthesis of compound 81.1. To a mixture of 74.1 (0.1 g, 0.258 mmol, 1.0eq) in 1,4-dioxane (2.5 mL) was added 67.3 (0.053 g, 0.258 mmol, 1.0 eq)and K₂CO₃ (0.089 g, 0.645 mmol, 2.5 eq). After degassing with argon for10 minutes, Pd₂(dba)₃ (0.024 g, 0.0258 mmol, 0.1 eq) and Xantphos (0.03g, 0.052 mmol, 0.2 eq) were added. Suspension was degassed foradditional 5 minutes then stirred at 100° C. for 2 hours. Aftercompletion of the reaction, mixture was poured into water and productwas extracted with EtOAc. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by column chromatographyto furnish 81.1 (0.09 g, 62.6%). MS(ES): m/z 557.63 [M+H]⁺.

Synthesis of compound I-81. To a solution of 81.1 (0.09 g, 0.16 mmol,1.0 eq) in CH₂Cl₂ (3.0 mL) was added TFA (0.5 mL). The reaction wasstirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into iced water, basified with satd. NaHCO₃and extracted with EtOAc. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by column chromatographyto furnish I-81 (0.04 g, 54.2%). MS(ES): m/z 457.51 [M+H]⁺; ¹H NMR(DMSO-d₆, 400 MHz): δ 9.04 (s, 1H), 8.77 (s, 1H), 7.85-7.83 (m, 1H),7.72-7.68 (m, 2H), 7.39-7.31 (m, 5H), 7.18 (s, 1H), 4.40 (s, 2H),3.07-3.01 (m, 2H), 1.43 (s, 6H), 0.96-0.92 (t, H).

Example 82. Synthesis of compound(S)-2-(2,6-difluorophenyl)-4-((5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-82

Compound I-82 was prepared by chiral separation of compound 1.78. MS(ES): m/z 450.37 [M+H]⁺, ¹H NMR (MeOD, 400 MHz): δ 8.81 (s, 1H), 8.56(d, 1H), 8.01-7.98 (m, 1H), 7.58-7.53 (m, 1H), 7.19-7.11 (m, 3H), 4.51(s, 2H), 1.76 (s, 3H).

Example 83. Synthesis of(R)-2-(2,6-difluorophenyl)-4-((5-(1,1,1-trifluoro-2-hydroxy-propan-2-yl)pyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-83

Compound I-83 was prepared by chiral separation of compound 1.78. MS(ES): m/z 450.37 [M+H]⁺; ¹H NMR (MeOD, 400 MHz): δ 8.80 (s, 1H),8.56-8.55 (d, 1H), 8.00-7.98 (m, 1H), 7.55 (m, 1H), 7.18-7.10 (m, 3H),4.50 (s, 2H), 1.76 (s, 3H).

Example 84. Synthesis of2-(2,6-difluorophenyl)-4-((4-(morpholine-4-carbonyl)phenyl)-amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine1-oxide, I-84

Synthesis of compound 84.1. Compound 53.1 (0.2 g, 0.53 mmol, 1.0 eq) andMCPBA (0.09, 0.53 mmol, 1.0 eq) were dissolved in CH₂Cl₂ (5.0 mL). Thereaction was stirred at 40° C. for 4 days. After completion of thereaction, mixture was poured into water and product was extracted withEtOAc. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude material.The crude was purified by column chromatography to furnish 84.1 (0.15 g,72.0%). MS(ES): m/z 396.77 [M+H]⁺.

Synthesis of compound 84.2. To a suspension of compound 84.1 (0.15 g,0.38 mmol, 1.0 eq) in 1,4-dioxane (3.0 ml) was added(4-aminophenyl)(morpholino)methanone (0.078 g, 0.378 mmol, 1.0 eq) andK₂CO₃ (0.156 g, 1.13 mmol, 3.0 eq). After degassing of the suspensionwith argon (10 minutes) Pd₂(dba)₃ (0.034 g, 0.037 mmol, 0.1 eq) andXantphos (0.043 g, 0.075 mmol, 0.2 eq) were added. Suspension wasdegassed for 5 minutes, the heated for 100° C. for 2 hours. Aftercompletion of the reaction, mixture was poured into water and productwas extracted with EtOAc. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by column chromatographyto provide 84.2 (0.05 g, 23.3%). MS(ES): m/z 566.56 [M+H]⁺.

Synthesis of compound I-84. To a solution of 84.2 (0.05 g, 0.088 mmol,1.0 eq) in CH₂Cl₂ (2.0 mL) was added TFA (0.5 mL). The reaction wasstirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into water, basified with satd. NaHCO₃ andextracted with EtOAc. Organic layers were combined, dried over Na₂SO₄and concentrated under reduced pressure to obtain crude which waspurified by column chromatography to furnish I-84 (0.020 g, 48.6%).MS(ES): m/z 466.44 [M+H]⁺; NMR (DMSO-d₆, 400 MHz): δ 9.08 (s, 1H), 9.05(s, 1H), 7.62 (m, 1H), 7.46-7.37 (m, 5H), 7.27-7.23 (t, 2H), 4.50 (s,2H), 3.58-3.38 (m, 8H).

Example 85. Synthesis of2-(4-((3,3-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3-fluorobenzonitrile,I-85

Synthesis of compound 85.2. To a solution of LDA (2.1 g, 21.0 mmol, 1.05eq) in THF (15.0 mL) was added n-BuLi (8.6 mL, 21.0 mmol, 1.05 eq) at−20° C. The reaction was stirred at same temperature for 1 hour.Compound 85.1 (2.0 g, 20.0 mmol, 1.0 eq) was added at −78° C. and thereaction was stirred for 3 hours. Then a solution of I₂ (5.3 g, 21.0mmol, 1.05 eq) in THF (15.0 mL) was added dropwise to the reactionmixture and the reaction was stirred for 1 hour. After completion of thereaction, mixture was poured into water and product was extracted withEtOAc. Organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain pure 85.2 (1.7g, 37.0%). MS(ES): m/z 222.99 [M+H]⁺.

Synthesis of compound 85.3. 2-methylprop-2-en-1-ol (0.32 g, 4.5 mmol,1.0 eq) was added to a solution of NaH (0.2 g, 9.0 mmol, 2.0 eq) in THF(10.0 mL). Compound 85.2 (1.0 g, 4.5 mmol, 1.0 eq) was added to themixture. Reaction was stirred at room temperature for 2 hours. Aftercompletion of the reaction, water was added to the reaction mixture andproduct was extracted with EtOAc. Organic layers were combined, washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain pure 85.3 (0.3 g, 24.3%). MS(ES): m/z 275.09 [M+H]⁺.

Synthesis of compound 85.4. Compound 85.3 (1.0 g, 3.6 mmol, 1.0 eq),TBAC (1.0 g, 3.6 mmol, 1.0 eq), sodium formate (0.24 g, 3.6 mmol, 1.0eq) and K₂CO₃ (1.5 g, 10.9 mmol, 3.0 eq) were mixed in DMF (10.0 mL) andsuspension was degassed with argon gas for 15 minutes. Pd(OAC)₂ (0.08 g,0.36 mmol, 0.1 eq) was added to the mixture and the reaction was stirred100° C. for 2 hours. After completion of the reaction, water was addedand product was extracted with EtOAc. Organic layers were combined,washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude material. The crude was purified by columnchromatography to furnish 85.4 (0.3 g, 55.3%). MS(ES): m/z 149.19[M+H]⁺.

Synthesis of compound 85.5. To a solution of 85.4 (0.23 g, 1.54 mmol,1.0 eq) in CH₂Cl₂ (5.0 mL) was added m-CPBA (0.39 g, 2.31 mmol, 1.5 eq)0° C. The reaction was stirred at room temperature for 2 hours. Aftercompletion of the reaction, mixture was poured in water and product wasextracted with CH₂Cl₂. Organic layers were combined, washed with brinesolution, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by column chromatographyto provide 85.5 (0.1 g, 39.3%). MS(ES): m/z 165.19 [M+H]⁺.

Synthesis of compound 85.6. Compound 85.5 (0.3 g, 1.81 mmol, 1.0 eq) wasdissolved in POCl₃ (5.0 mL) and the reaction was stirred at 100° C. for6 hours. After completion of the reaction, mixture was quenched withsatd. NaHCO₃ then extracted with EtOAc. Organic layers were combined,washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude material. The crude was purified by columnchromatography to furnish 85.6 (0.1 g, 30.0%). MS(ES): m/z 183.64[M+H]⁺.

Synthesis of compound 85.7. To a solution of compound 85.6 (0.06 g,0.327 mmol, 1.0 eq) in 1,4-dioxane (1 ml) was added 2,4-dimethoxy benzylamine (0.082 g, 0.149 mmol, 1.5 eq) and Cs₂CO₃ (0.319 g, 0.98 mmol, 3.0eq). The reaction mixture was degassed for 10 minutes with argon, thenPd₂(dba)₃ (0.03 g, 0.032 mmol, 0.1 eq) and2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.025 g, 0.065mmol, 0.2 eq) were added. The reaction was then stirred at 100° C. for 2hours. After completion of the reaction, mixture was poured into waterand product was extracted with EtOAc. Organic layers were combined,dried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude material. The crude was purified by column chromatography tofurnish 85.7 (0.04 g, 43.4%). MS (ES): m/z 282.39 [M+H]⁺.

Synthesis of compound 85.8. Compound 85.7 (0.03 g, 0.106 mmol, 1.0 eq)was dissolved in TFA (1.0 mL). The reaction was stirred at 60° C. for 2hours. After completion of the reaction, mixture was quenched with satd.NaHCO₃ solution and product was extracted with EtOAc. Organic layerswere combined, washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain pure 85.8 (0.020 g, 99.0%). MS(ES): m/z164.21 [M+H]⁺.

Synthesis of compound 85.9. To a mixture of 74.1 (0.047 g, 0.12 mmol,1.0 eq) in 1,4-dioxane (3.0 ml) was added compound 85.8 (0.020 g, 0.12mmol, 1.0 eq) and K₂CO₃ (0.05 g, 0.36 mmol, 3.0 eq). The reactionmixture was degassed for 10 minutes with argon then Pd₂(dba)₃ (0.011 g,0.012 mmol, 0.1 eq) and xantphos (0.013 g, 0.024 mmol, 0.2 eq) wereadded and again degassed for 5 minutes. The reaction was stirred at 100°C. for 2 hours. After completion of the reaction, mixture was pouredinto water and product was extracted with EtOAc. Organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude material. The crude was purified bycolumn chromatography to furnish 85.9 (0.04 g, 64.0%). MS(ES): m/z515.55 [M+H]⁺.

Synthesis of compound I-85. To a solution of 85.9 (0.04 g, 0.077 mmol,1.0 eq) in CH₂Cl₂ (1.0 mL) was added TFA (1.0 mL) The reaction wasstirred at room temperature for 1 hour. After completion of thereaction, mixture was poured into water, basified with satd. NaHCO₃ andproduct was extracted with EtOAc. Organic layer were combined and driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudematerial. The crude was purified by column chromatography to provideI-85 (0.02 g, 62.1%). MS(ES): m/z 415.43 [M+H]⁺; ¹H NMR (DMSO-d₆, 400MHz): δ 9.40 (s, 1H), 9.01 (s, 1H), 7.93-7.87 (m, 2H), 7.77-7.72 (m,2H), 7.58 (s, 1H), 7.18-7.16 (d, 1H), 4.49 (s, 2H), 4.25 (s, 2H), 1.49(s, 6H).

Example 86. Synthesis of2-(2,6-difluorophenyl)-4-((2,2-dioxido-1,3-dihydro-benzo[c]thio-phen-5-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,I-86

Synthesis of compound 86.2. To a solution of 86.1 (1.6 g, 6.06 mmol, 1.0eq) in benzene (8.0 mL) was added solution of sodium sulfide monohydrate(2.9 g, 12.1 mmol, 2.0 eq) in water (30 mL) followed by Benz triethylammonium chloride (catalytic). The reaction was stirred at 20° C. for 30hours. After completion of the reaction, mixture was poured into waterand extracted with CH₂Cl₂. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain 86.2 (0.7 g, 84.7%). Crude product was used for next step withoutany further purification.

Synthesis of compound 86.3. To 86.2 (0.7 g, 5.14 mmol, 1.0 eq) was addedAcOH (4.3 mL) at 5-10° C. Solution was stirred for 1 hour. To thissolution was added 30% H₂O₂ solution (1.2 mL). Reaction mixture stirredat 90-95° C. for 3 hours. After completion of the reaction, mixture waspored into water and product was extracted with EtOAc. Organic layerswere combined, washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure to get crude material. The crude was purified bycolumn chromatography to provide 86.3 (0.3 g, 34.7%). ¹H NMR (CDCl₃, 400MHz): δ 7.40-7.28 (m, 4H), 4.4 (s, 4H).

Synthesis of compound 86.4. To a solution of 86.3 (0.2 g, 1.19 mmol, 1.0eq) in concentrated H₂SO₄ (2.0 mL) at 0° C. was added HNO₃ (1.0 mL)slowly. Reaction was stirred at 0° C. for 30 minutes. After completionof the reaction, mixture was transferred into crushed ice and productwas extracted with EtOAc. Organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure to getcrude material. The crude was purified by column chromatography tofurnish 86.4 (0.12 g, 47.3%). ¹H NMR (CDCl₃, 400 MHz): δ8.3-8.26 (m,2H), 7.58-7.54 (d, 1H), 4.51-4.48 (d, 4H).

Synthesis of compound 86.5. To the suspension of 10% Pd/C (0.03 g) inMeOH (3.0 mL) was added compound 86.4 (0.12 g, 0.56 mmol, 1.0 eq).Suspension was purged with H₂ gas for 1 hour. Reaction mixture filteredthrough celite and concentrated under reduced pressure to obtain 86.5(0.08 g, 77.5%). MS(ES): m/z 184.1 [M+H]⁺.

Synthesis of compound 86.6. To a mixture of 74.1 (0.080 g, 0.21 mmol,1.0 eq) in 1,4-dioxane (3.0 ml) was added 86.5 (0.046 g, 0.21 mmol, 1.0eq) and K₂CO₃ (0.073 g, 0.53 mmol, 2.5 eq). The reaction mixture wasdegassed for 10 minutes using argon then Pd₂(dba)₃ (0.019 g, 0.021 mmol,0.1 eq) and Xantphos (0.024 g, 0.042 mmol, 0.2 eq) were added, and againdegassed for 5 minutes. The reaction was stirred at 120° C. for 2 hours.After completion of the reaction, mixture was transferred into water andproduct was extracted with EtOAc. Organic layers were combined, washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude material. The crude was purified by column chromatographyto furnish 86.6 (0.08 g, 72.2%). MS(ES): m/z 528.6 [M+H]⁺.

Synthesis of compound I-86. Compound 86.6 (0.08 g, 0.151 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (1.0 mL) and TFA (0.5 mL) was added to thereaction mixture. The reaction was stirred at room temperature for 1hour. After completion of the reaction, mixture was poured into water,basified with satd. NaHCO₃ and product was extracted with EtOAc. Organiclayers were combined, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude material. The crude was purified by columnchromatography to provide (0.05 g, 77.1%). MS(ES): m/z 428.57 [M+H]⁺;NMR (DMSO-d₆, 400 MHz): δ 9.10 (s, 1H), 8.75 (s, 1H), 7.55-7.51 (m, 1H),7.43-7.34 (m, 2H), 7.22-7.18 (m, 2H), 7.08 (s, 1H), 5.76 (s, 1H),4.57-4.46 (d, 4H), 4.37 (s, 2H).

Example 87. Synthesis of3-fluoro-2-(4-((5-(4-hydroxy-9-azadispiro[2.1.25.33]decan-9-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile,I-87

Synthesis of compound 87.2. Methyl Iodide (46.2 g, 45.2 mmol, 1.0 eq)was added to 87.1 (5.0 g, 325 mmol, 1.1 eq). Reaction mixture wasstirred at room temperature for 48 hours. After completion of thereaction, solid were filtered off and washed with Et₂O to get pure 87.2(5.2 g, 91.6%). ¹H NMR (DMSO-d₆, 400 MHz): δ 4.15-4.12 (t, 2H),3.80-3.77 (t, 2H), 2.97 (s, 6H).

Synthesis of compound 87.4. KOBu^(t) (0.675 g, 6.03 mmol, 1.0 eq) wasadded to t-Butanol (10 mL) and heated to 60° C. To this solution wasadded 87.3 (1.2 g, 6.03 mmol, 1.0 eq) and stirred at room temperaturefor 1 h. To the mixture was added 87.2 (1.36 g, 5.4 mmol, 0.9 eq)portion wise and resulting mixture was stirred at room temperature for 2hours. To this mixture was added solution of KOBu^(t) (0.68 g, 6.03mmol, 1.0 eq) in t-Butanol (10 mL) and reaction was stirred at roomtemperature for 48 hours. After completion of the reaction, mixture waspoured into water and product was extracted with EtOAc. Organic layerswere combined, dried over Na₂SO₄ and concentrated under reduced pressureto obtain crude material. The crude was purified by columnchromatography to provide 87.4 (0.2 g, 13.2%). ¹H NMR (CDCl₃, 400 MHz):δ 3.76 (s, 4H), 1.49 (s, 9H), 1.3-1.26 (m, 4H), 0.87 (bs, 4H).

Synthesis of compound 87.5. To a solution of 87.5 (0.2 g, 0.79 mmol, 1.0eq) in CH₂Cl₂ (5.0 mL) was added TFA (0.9 g, 7.96 mmol, 10 eq) at 0° C.Reaction was stirred for 2 hours. After completion of the reaction,solvent was concentrated under reduced pressure and neutralised withsatd. NaHCO₃ solution. Mixture was extracted with CH₂Cl₂, organic layerswere combined, dried over Na₂SO₄ and concentrated under reduced pressureto obtain 87.5 (0.11 g, 91.4%). ¹H NMR (CDCl₃, 400 MHz): δ 3.12 (s, 4H),1.34-1.31 (m, 4H), 0.75-0.73 (m, 4H).

Synthesis of compound 87.6. To a solution of 87.5 (0.11 g, 0.728 mmol,1.0 eq) in DMSO (5.0 mL) was added 5-fluoro-2-nitropyridine (0.103 g,0.728 mmol, 1.0 eq) followed by DIPEA (0.94 g, 7.28 mmol, 10 eq).Reaction mixture was stirred at 100° C. for 2 hours. After completion ofthe reaction, mixture was transferred into water and extracted withEtOAc. Organic layers were combined, dried over Na₂SO₄ and concentratedunder reduced pressure to obtain 87.6 (0.1 g, 50.3%). MS(ES): m/z 274.3[M+H]⁺.

Synthesis of compound 87.7. To a solution of 87.6 (0.1 g, 0.366 mmol,1.0 eq) in MeOH (3.0 mL) was added NaBH₄ (0.070 g, 1.83 mmol, 5.0 eq) at0° C. Reaction mixture was stirred at room temperature for 1 hour. Aftercompletion, the reaction was quenched with saturated NH₄Cl solution andextracted with CH₂Cl₂. Organic layers were combined, dried over Na₂SO₄and concentrated under reduced pressure to obtain crude material whichwas triturated with n-hexane to provide 87.7 (0.075 g, 79.0%). MS(ES):m/z 276.38 [M+H]⁺.

Synthesis of compound 87.8. To the suspension of 10% Pd/C (0.05 g) inMeOH (3.0 mL) was added compound 87.7 (0.075 g, 0.272 mmol, 1.0 eq) andpurged with H₂ gas for 2 hours. Reaction mixture was filtered throughcelite and concentrated under reduced pressure to obtain 87.8 (0.06 g,89.8%). MS(ES): m/z 246.37 [M+H]⁺.

Synthesis of compound 87.9. To a solution 74.1 (0.090 g, 0.232 mmol, 1.0eq) in 1,4-dioxane (2.0 ml) was added 87.8 (0.051 g, 0.208 mmol, 1.0 eq)and K₂CO₃ (0.080 g, 0.58 mmol, 2.5 eq). The reaction mixture wasdegassed for 10 minutes using argon then Pd₂(dba)₃ (0.021 g, 0.023 mmol,0.1 eq) and Xantphos (0.026 g, 0.046 mmol, 0.2 eq) were added and againdegassed for 5 minutes. The reaction was stirred at 110° C. for 2 hours.After completion of the reaction, mixture was poured into water andproduct was extracted with EtOAc. Organic layers were combined, driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudematerial. The crude was purified by column chromatography to furnish87.9 (0.07 g, 55.5%). MS(ES): m/z 597.6 [M+H]⁺.

Synthesis of compound I-87. Compound 87.9 (0.070 g, 0.117 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (2.0 mL) and TFA (0.5 mL) was added to thereaction mixture. The reaction was stirred at room temperature for 1hour. After completion of the reaction, mixture was poured into water,basified with satd. NaHCO₃ solution and extracted with EtOAc. Organiclayers were combined, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude. The crude was purified by columnchromatography to furnish I-87 (0.030 g, 51.3%). MS (ES): m/z 497.7[M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.52 (s, 1H), 8.86 (s, 1H), 8.47(s, 1H), 7.96 (d, 1H), 7.89-7.86 (dd, 1H), 7.8-7.72 (m, 2H), 7.41-7.38(dd, 1H), 7.09-7.07 (d, 1H), 4.63 (d, 1H), 4.42 (s, 2H), 3.23-3.20 (d,2H), 2.79-2.76 (d, 2H), 0.46 (s, 6H), 0.34-0.32 (d, 2H).

Example 88. Synthesis of3-fluoro-2-(4-((5-((3R,5R)-3-hydroxy-1-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile.I-88

Synthesis of compound 88.2. To a stirred mixture of 88.1 (4.0 g, 21.5mmol, 1.0 eq) and 3-bromoprop-1-ene (4.7 mL, 53.9 mmol, 2.5 eq) in THF(10.0 mL) was added saturated NH₄Cl solution (20.0 mL). To thesuspension was slowly added zinc dust (2.8 g, 43.1 mmol, 2.0 eq) whilemaintaining temperature below 40° C. The reaction mixture was stirred atroom temperature for 12 hours. After completion of the reaction, 10% aq.H₂SO₄ was slowly added. Reaction mixture was filtered and the productwas extracted with EtOAc. Organic layers were separated, washed withbrine solution and dried over Na₂SO₄, concentrated under reducedpressure to provide 88.2 (4.3 g 87.6%). ¹H NMR (DMSO-d₆, 400 MHz): δ5.91-5.83 (m, 1H), 5.24-5.19 (m, 2H), 3.55-3.48 (m, H), 3.41-3.25 (m,2H), 2.42-2.40 (d, 2H), 1.89-1.85 (t, 2H), 1.47 (s, 9H).

Synthesis of compound 88.3. To a stirred mixture of 88.2 (4.3 g, 18.9mmol, 1.0 eq) and NaIO₄ (4.0 g, 18.9 mmol, 1.0 eq) in t-Butanol (28 mL)and water (9.4 mL) was added solution of sodium metabisulphite (3.59 g,18.9 mmol, 1.0 eq) in water (15.0 mL) at 50° C. Reaction mixture wasstirred at 50° C. for 12 hour followed by 10 hours at room temperature.After completion of the reaction, reaction mixture cooled to roomtemperature and extracted with EtOAc. Organic layers were combined,washed with brine, dried over sodium sulphate and concentrated underreduced pressure to obtain crude material which was purified by columnchromatography, to provide 88.3 (1.0 g, 21.7%). MS(ES): m/z 244.3[M+H]⁺.

Synthesis of compound 88.4. To a stirred solution of 88.3 (0.38 g, 1.56mmol, 1.0 eq) in CH₂Cl₂ (5.0 mL) was added TFA (1.0 mL) and reactionmixture was stirred at room temperature for 2 hours. Reaction mixturewas concentrated under reduced pressure to obtain crude 88.4 (0.3 g,80.0%), MS(ES): m/z 144.17 [M+H]⁺.

Synthesis of compound 88.5. To a stirred mixture of 88.4 (0.12 g, 0.84mmol, 1.2 eq) and 5-fluoro-2-nitropyridine (0.1 g, 0.70 mmol, 1.0 eq) inDMSO (2.0 mL) was added DIPEA (0.92 g, 7.03 mmol, 10.0 eq) and heated at90° C. for 5 hours. Reaction mixture was cooled to room temperature,poured into water and extracted with EtOAc. Organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to obtain crude which was purified by columnchromatography to furnish 88.5 (0.125 g, 64.3%). MS(ES): m/z 266.33[M+H]⁺.

Synthesis of compound 88.6. To a suspension of 10% Pd/C (0.05 g) in MeOH(5.0 mL) was added compound 88.5 (0.125 g, 0.471 mmol, 1.0 eq).Suspension was purged with H₂ gas for 1 hour. Reaction mixture filteredthrough celite and concentrated under reduced pressure to obtain 88.6(0.10 g, 94.0%). MS(ES): m/z 236.37 [M+H]⁺.

Synthesis of compound 88.7. To a mixture of 74.1 (0.075 g, 0.193 mmol,1.0 eq) in 1,4-dioxane (2.0 mL) was added 88.5 (0.049 g, 0.212 mmol, 1.1eq) and K₂CO₃ (0.079 g, 0.579 mmol, 3.0 eq). The reaction mixture wasdegassed for 10 minutes using argon then Pd₂(dba)₃ (0.017 g, 0.019 mmol,0.1 eq) and Xantphos (0.022 g, 0.038 mmol, 0.2 eq) were added and againdegassed for 5 minutes. The reaction was stirred at 100° C. for 2 hours.After completion of the reaction, mixture was poured into water andproduct was extracted with EtOAc. Organic layers were combined, washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toobtain crude. This was purified by column chromatography to furnish 88.7(0.058 g, 23.3%). MS(ES): m/z 587.58 [M+H]⁺.

Synthesis of compound 88.8. Diastereomeric mixture 88.7 (0.058 g) wasseparated using reverse phase column (X-BRIDGE C18 250×19 mm, 5μ) toafford to afford pure 88.8 (0.023 g), MS (ES): 587.3 [M+H]⁺

Synthesis of compound I-88. Compound 88.8 (0.023 g, 0.039 mmol, 1.0 eq)was dissolved in CH₂Cl₂ (2.0 mL) and TFA (0.2 mL) was added. Thereaction mixture was stirred at room temperature for 2 hours. Aftercompletion of the reaction, mixture was poured into water, basified withsatd. NaHCO₃ and extracted with CH₂Cl₂. Organic layers were combined,washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude which was purified trituration with n-pentaneto get pure I-88 (0.010 g, 52.4%). MS(ES): m/z 487.2 [M+H]⁺; ¹H NMR(DMSO-d₆, 400 MHz): δ 9.42 (s, 1H), 8.81 (s, 1H), 8.31 (s, 1H),7.88-7.85 (m, 1H), 7.79-7.69 (m, H), 7.65-7.64 (d, 1H), 7.11-7.09 (d,1H), 7.01-6.98 (dd, 1H), 4.96 (d, 1H), 4.40 (s, 2H), 4.35 (s, 1H),3.83-3.79 (m, 1H), 3.60-3.57 (dd, 1H), 3.29 (s, 1H), 3.25 (s, H),2.20-2.13 (m, 2H), 2.08-2.00 (m, 1H), 1.88-1.84 (dd, 1H).

Example 89. Synthesis of3-fluoro-2-(4-((5-((3S,5R)-3-hydroxy-1-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile,I-89

Compound I-89 was prepared from 88.7 using procedure described inExample 89. MS(ES): m/z 487.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.43(s, 1H), 8.81 (s, 1H), 8.31 (s, 1H), 7.87-7.85 (m, 1H), 7.78-7.70 (m,2H), 7.64 (d, 1H), 7.11-7.09 (d, 1H), 7.01-6.98 (dd, 1H), 4.97 (d, 1H),4.40 (s, 2H), 4.35 (s, 1H), 3.86-3.82 (m, 1H), 3.59-3.56 (dd, 1H), 3.38(s, 1H), 3.26 (s, 2H), 2.12-2.08 (m, 1H), 2.01-1.98 (m, 2H), 1.94-1.90(dd, 1H).

Example 90. Synthesis of3-fluoro-2-(4-((5-((3R,5R)-3-hydroxy-1-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile,I-90

Compound I-90 was prepared by chiral separation of compound I-88.MS(ES): m/z 487.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.43 (s, 1H),8.82 (s, 1H), 8.32 (s, 1H), 7.88-7.86 (dd, 1H), 7.79-7.71 (m, H), 7.65(d, 1H), 7.12-7.09 (d, 1H), 7.02-6.99 (dd, 1H), 4.96 (d, 1H), 4.41 (s,2H), 4.35 (s, 1H), 3.83-3.79 (m, 1H), 3.60-3.58 (dd, 1H), 3.29 (s, 1H),3.25 (s, 2H), 2.18-2.12 (m, 2H), 2.09-2.03 (m, 1H), 1.89-1.85 (dd, 1H).

Example 91. Synthesis of3-fluoro-2-(4-((5-((3S,5S)-3-hydroxy-1-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile,I-91

Compound I-91 was prepared by chiral separation of compound I-88.MS(ES): m/z 487.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): 9.42 (s, 1H), 8.82(s, 1H), 8.32 (s, 1H), 7.88-7.86 (dd, 1H), 7.79-7.71 (m, 2H), 7.65 (d,1H), 7.11-7.09 (d, 1H), 7.01-6.98 (dd, 1H), 4.98 (s, 1H), 4.41 (s, 2H),4.35 (s, 1H), 3.83-3.80 (m, 1H), 3.61-3.58 (dd, 1H), 3.29 (s, 1H), 3.25(s, 2H), 2.18-2.12 (m, 2H), 2.09-2.03 (m, 1H), 1.89-1.85 (dd, 1H).

Example 92. Synthesis of3-fluoro-2-(4-((5-((3R,5S)-3-hydroxy-1-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile,I-92

Compound I-92 was prepared by chiral separation of compound I-89.MS(ES): m/z 487.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.43 (s, 1H),8.81 (s, 1H), 8.32 (s, 1H), 7.88-7.86 (dd, 1H), 7.77-7.71 (m, 2H),7.65-7.64 (d, 1H), 7.11-7.09 (d, 1H), 7.01-6.98 (dd, 1H), 4.98-4.97 (d,1H), 4.41 (s, 2H), 4.35 (s, 1H), 3.86-3.82 (m, 1H), 3.59-3.56 (dd, 1H),3.30 (s, 2H), 3.25 (s, 2H), 2.13-2.08 (m, 1H), 2.02-1.99 (m, 2H),1.94-1.90 (dd, 1H).

Example 93. Synthesis of3-fluoro-2-(4-((5-((3S,5R)-3-hydroxy-1-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile,I-93

Compound I-93 was prepared by chiral separation of compound I-89.MS(ES): m/z 487.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 9.43 (s, 1H),8.81 (s, 1H), 8.32 (s, 1H), 7.87-7.85 (d, 1H), 7.77-7.71 (m, 2H),7.65-7.64 (d, 1H), 7.11-7.09 (d, 1H), 7.01-6.98 (dd, 1H), 4.97 (s, 1H),4.41 (s, 2H), 4.36 (s, 1H), 3.86-3.83 (m, 1H), 3.59-3.57 (dd, 1H), 3.29(s, 1H), 3.26 (s, 2H), 2.13-2.08 (m, 1H), 2.02-2.00 (m, 2H), 1.94-1.91(dd, 1H).

Example 94: Tyk2 & JAK2 Radioactive Kinase Assay

Peptide substrate, [KKSRGDYMTMQIG], (20 μM) is prepared in reactionbuffer (20 mM Hepes pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35, 0.02mg/mL BSA, 0.1 mM Na₃PO₄, 2 mM DTT, 1% DMSO. TYK2 (Invitrogen) kinase isadded, followed by compounds in DMSO. 33PATP is added to initiate thereaction in ATP at 10 μM. Kinase reaction is incubated for 120 min atroom temp and reactions are spotted onto P81 ion exchange paper (Whatman#3698-915), and then washed extensively in 0.75% phosphoric acid, priorto reading the radioactivity counts. For JAK2 (Invitrogen) kinase assaythe peptide substrate poly[Glu:Tyr](4:1), 0.2 mg/ml is used, in thereaction carried out the same as for TYK2.

Example 95: Tyk2 & JAK2 Caliper Assay

The caliper machine employs an off chip mobility shift assay to detectphosphorylated peptide substrates from kinase assays, usingmicrofluidics technology. The assays are carried out at ATPconcentration equivalent to the ATP Km, and at 1 mM ATP. Compounds areserially diluted in DMSO then further diluted in assay buffer (25 mMHEPES, pH 7.5, 0.01% Brij-35, 0.01% Triton, 0.5 mM EGTA). 5 ul ofdiluted compound was added into wells first, then 10 ul of enzyme mixwas added into wells, followed by 10 uL of substrate mix (peptide andATP in 10 mM MgCl₂) to start reaction. Reaction was incubated at 28° C.for 25 min and then added 25 ul stop buffer (100 mM HEPES, 0.015%Brij-35, 50 mM EDTA), followed by reading with Caliper. JAK2 at 1 nMfinal concentration and TYK2 at 9.75 nM are from Cama, and substratesused are ATP at 20 and 16 uM, respectively. JAK2 assay uses peptide 22and TYK2 uses peptide 30 (Caliper), each at 3 uM.

Table 2 shows the activity of selected compounds of this invention inthe Tyk2 and JAK2 activity inhibition assay. The compound numberscorrespond to the compound numbers in Table 1. Compounds having anactivity designated as “A” provided an Ki≤0.01 μM; compounds having anactivity designated as “B” provided an Ki of 0.01-0.1 μM; compoundshaving an activity designated as “C” provided an Ki of 0.1-1.0 μM; andcompounds having an activity designated as “D” provided an Ki≥1.0 μM.

TABLE 2 Tyk2 & JAK2 Activity Inhibition Data Compound # Tyk2 Ki JAK2 KiI-1 A C I-2 A B I-3 A C I-4 A B I-5 A C I-6 A C I-7 A C I-8 A C I-9 B BI-10 A B I-12 A C I-13 B C I-14 A C I-15 A B I-16 A C I-17 A B I-18 A BI-19 B D I-20 A B I-21 A B I-22 A B I-23 A C I-24 A A I-25 A B I-26 A CI-27 A B I-28 A C I-29 A C I-30 A C I-31 A B I-32 A D I-33 A C I-34 A BI-35 A C I-36 A B I-37 A A I-38 A A I-39 A C I-40 C D I-41 C C I-42 A BI-43 A B I-44 A C I-45 A C I-46 B C I-47 A A I-48 B C I-48 A B I-50 A BI-51 A A I-52 A A I-53 A B I-54 A B I-55 A A I-56 B C I-57 A B I-58 A AI-59 A B I-60 A B I-61 B D I-62 A B I-63 A B I-64 A B I-65 A A I-66 A BI-67 A A I-68 B C I-69 B D I-70 A C I-71 B C I-72 B D I-73 B D I-74 A CI-75 A A I-76 A B I-77 A B I-78 A B I-79 A B I-80 A B I-81 A A I-82 A AI-83 A A I-84 B D I-85 D D I-86 A B I-87 A A I-88 A A I-89 A A I-90 A AI-91 A A I-92 A B I-93 A B

IL-12 Induced pSTAT4 in human PBMC. Human PBMC are isolated from buffycoat and are stored frozen for assays as needed. Cells for assay arethawed and resuspended in complete media containing serum, then cellsare diluted to 1.67 E6 cells/ml so that 120 μl per well is 200,000cells. 15 μl of compound or DMSO is added to the well at the desiredconcentrations and incubated at 1 hr at 37 C. 15 μl of stimulus (finalconcentration of 1.7 ng/mL IL-12) is added for 30 minutes prior topSTAT4 and total STAT4 analysis using cell lysates prepared and analyzedby MSD reagents as per manufacturer protocol. The final DMSOconcentration of compound in the assay is 0.1%.

GM-CSF Induced pSTAT5 in human PBMC. Cells are prepared for analysis asin the above procedure and 15 μl of GM-CSF (final concentration 5 ng/mL)is added for 20 minutes prior to pSTAT5 and total STAT5 analysis usingcell lysates prepared and analyzed by MSD reagents as per manufacturerprotocol. The final DMSO concentration of compound in the assay is 0.1%.

Table 3 shows the activity of selected compounds of this invention inthe IL-12 induced pSTAT4 and GM-CSF induced pSTAT5 inhibition assays inhuman PBMC. The compound numbers correspond to the compound numbers inTable 1. Compounds having an activity designated as “A” provided anEC₅₀≤2 μM; compounds having an activity designated as “B” provided aEC₅₀ of 2-20 μM; and compounds having an activity designated as “C”provided an EC₅₀>20 μM.

TABLE 3 Cell activity data Compound # Tyk2-pSTAT4 EC₅₀ JAK2-pSTAT5 EC₅₀I-1 A B I-2 A B I-4 A A I-10 A A I-15 A B I-17 A B I-18 A B I-20 A CI-25 A B I-34 A B I-36 A B I-52 A A I-58 A B I-59 A B I-60 A B I-62 A AI-65 A B I-67 A B I-70 A C I-72 C C I-75 A B I-79 A B I-84 C C I-88 A AI-89 A A I-91 A A I-93 A B

Acute Mouse Model for IL-12/IL-18 Induced IFNγ in serum—C57BL/6 micemice are dosed PO or SC with test compound at various doses or vehicle(n=9 or 10 per group) and then, 30 minutes later, injected IP with 10 ngIL-12 and 1 μg IL-18. Three hours after IL-12/IL-18 injection, mice arebled and serum isolated. Concentration of cytokines in serum aredetermined using CBA analysis.

Certain compounds of the invention inhibit ˜50% of the IL-12/IL-18induced IFNγ production in vivo.

Ex vivo Mouse IL-12 induced IFNγ Studies C57/BL6 mice are given a singleoral dose of either vehicle or different doses of compound at a volumeof 10 mL/kg. 30 minutes to 1 hour after dosing, animals are euthanizedand blood was collected via vena cava into sodium heparin bloodcollection tubes and inverted several times. Blood is then plated onanti-CD3 coated plates and stimulated with 2 ng/ml of mouse IL-12 inRPMI media for 24 hours at 37° C. in humidified incubator with 5% CO₂.At the end of the incubation, blood is centrifuged at 260 g for 5minutes to collect supernatant. IFNγ concentration in the supernatant isdetermined with mouse IFNγ MSD kit per manufacture's instruction (MesoScale Discovery). At the time of the blood collection, plasma iscollected for drug level analysis by LC-MS/MS.

Certain compounds of the invention inhibit IL-12 induced IFNγ productionin the ex-vivo mouse model.

T-ALL Cell Proliferation Assay T-ALL cell lines KOPT-K1, HPB-ALL,DND-41, PEER, and CCRF-CEM are cultured in RPMI-1640 medium with 10%fetal bovine serum and penicillin/streptomycin. Cells are plated intriplicate at 1×10⁴ cells per well in 96-well plates. T-ALL cell linesDU. 528, LOUCY, and SUP-T13 are cultured in the same medium and platedat a density of 1.5×10⁴ cells per well. The cells are treated with DMSOor different concentrations of each compound of the invention. Cellviability at 72 hour exposure to the drug is assessed by CellTiter-GloLuminescent Cell Viability Assay (Promega). CellTiter-Glo Reagent isadded into the well and incubated for 10 minutes. Luminescence ismeasured subsequently using a 96-well plate luminescence reader. Cellviability is calculated by using the DMSO treated samples as 100%. IC₅₀value is calculated by nonlinear regression using GraphPad Prismsoftware.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim: 1-3. (canceled)
 4. A compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein: each of X and Yis independently ═C(R⁶)—, ═N—, or ═N⁺(→O⁻)—, provided that X and Y arenot simultaneously ═C(R⁶)—; Ring A is phenyl; a 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; a 3-6 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; or a 4-6 membered saturated or partiallyunsaturated carbocyclic ring; wherein Ring A is substituted with minstances of R⁷; each R² is independently an optionally substitutedgroup selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, and a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; R³ is a group selected from C₁₋₆alkyl, phenyl, a 3-7 membered saturated or partially unsaturatedcarbocyclic ring, a 3-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; wherein R³ is substituted with n instances of R⁸; R⁴ is hydrogenor optionally substituted C₁₋₆ aliphatic; or R⁴ and one instance of R⁷are taken together with their intervening atoms to form a 5-6 memberedpartially unsaturated or aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen and sulfur; R⁵ is a groupselected from halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂,—S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, phenyl, a 3-14membered saturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; wherein R⁵ is substitutedwith p instances of R⁹; R⁶ is hydrogen, —R², halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R; each instance of R⁷, R⁸, R¹⁰, and R¹¹ is independentlyoxo, —R², halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R,—S(O)₂NR_(2J)—S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R,—OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R; eachinstance of R⁹ is independently oxo, C₁₋₆ hydroxyaliphatic, —R²,halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR_(2J)—S(O)R,—C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R; L¹ is a covalent bond or aC₁₋₆ bivalent saturated or unsaturated, straight or branched hydrocarbonchain wherein one or two methylene units of the chain are optionally andindependently replaced by —C(R¹⁰)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—,—N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or—S(O)₂—; or L¹ and one instance of R⁷ are taken together with theirintervening atoms to form a 5-10 membered partially unsaturated oraromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, sulfur, and boron; wherein said ring is substituted byq instances of R¹¹; and R⁵ is attached to any position of the ringformed by L¹ and R⁷; m is 0-4; n is 0-4; p is 0-6; q is 0-4; and each Ris independently hydrogen, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partiallyunsaturated heterocyclic having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or: two R groups on the same nitrogen are taken together withtheir intervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, and sulfur.5. The compound of claim 4, wherein Ring A is phenyl, pyridin-2-yl,pyridine-3-yl, or pyrazol-4-yl.
 6. The compound of claim 5, wherein RingA is pyridin-2-yl.
 7. The compound of claim 4, wherein X is ═C(R⁶)—; andY is ═N—.
 8. The compound of claim 7, wherein R⁶ is hydrogen.
 9. Thecompound of claim 4, wherein L¹ is —CH₂C(O)—, —C(O)—, or a covalentbond.
 10. The compound of claim 9, wherein L¹ is —C(O)—.
 11. Thecompound of claim 9, wherein L¹ is a covalent bond.
 12. The compound ofclaim 4, wherein R³ is phenyl, pyrrolidinyl, or piperidinyl.
 13. Thecompound of claim 12, wherein R³ is phenyl.
 14. The compound of claim 4,wherein wherein n is 2, and at least one R⁸ is fluoro.
 15. (canceled)16. A pharmaceutical composition comprising a compound of claim 4, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle. 17-36. (canceled)
 37. Thecompound of claim 5, wherein Ring A is phenyl.
 38. The compound of claim5, wherein Ring A is pyridine-3-yl.
 39. The compound of claim 5, whereinRing A is pyrazol-4-yl.
 40. The compound of claim 4, wherein X is ═N—and Y is ═N—.
 41. The compound of claim 4, wherein X is ═N— and Y is═C(R⁶)—.
 42. The compound of claim 9, wherein L¹ is —CH₂C(O)—.
 43. Thecompound of claim 12, wherein R³ is pyrrolidinyl.
 44. The compound ofclaim 12, wherein R³ is piperidinyl.